
==== Front
Redox Biol
Redox Biol
Redox Biology
2213-2317
Elsevier

S2213-2317(24)00318-5
10.1016/j.redox.2024.103340
103340
Review Article
Role of mitochondria in reno-cardiac diseases: A study of bioenergetics, biogenesis, and GSH signaling in disease transition
Lumpuy-Castillo Jairo jairo.lumpuy@estudiante.uam.e
a1
Amador-Martínez Isabel amador_i@ciencias.unam.mx
bc1
Díaz-Rojas Miriam diaz.530@osu.edu
d
Lorenzo Oscar olorenzo@fjd.es
a
Pedraza-Chaverri José pedraza@unam.mx
c
Sánchez-Lozada Laura Gabriela laura.sanchez@cardiologia.org.mx
b
Aparicio-Trejo Omar Emiliano omar.aparicio@cardiologia.org.mx
emilianoaparicio91@gmail.com
b⁎
a Laboratory of Diabetes and Vascular Pathology, IIS-Fundación Jiménez Díaz-Ciberdem, Medicine Department, Autonomous University, 28040, Madrid, Spain
b Department of Cardio-Renal Physiopathology, National Institute of Cardiology Ignacio Chávez, 14080, Mexico City, Mexico
c Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, 04510, Mexico City, Mexico
d Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 43210, Columbus, Ohio, USA
⁎ Corresponding author. omar.aparicio@cardiologia.org.mxemilianoaparicio91@gmail.com
1 Both authors contributed equally to this manuscript.

05 9 2024
10 2024
05 9 2024
76 10334018 7 2024
1 9 2024
2 9 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health burdens with rising prevalence. Their bidirectional relationship with cardiovascular dysfunction, manifesting as cardio-renal syndromes (CRS) types 3 and 4, underscores the interconnectedness and interdependence of these vital organ systems. Both the kidney and the heart are critically reliant on mitochondrial function. This organelle is currently recognized as a hub in signaling pathways, with emphasis on the redox regulation mediated by glutathione (GSH). Mitochondrial dysfunction, including impaired bioenergetics, redox, and biogenesis pathways, are central to the progression of AKI to CKD and the development of CRS type 3 and 4. This review delves into the metabolic reprogramming and mitochondrial redox signaling and biogenesis alterations in AKI, CKD, and CRS. We examine the pathophysiological mechanisms involving GSH redox signaling and the AMP-activated protein kinase (AMPK)-sirtuin (SIRT)1/3-peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis in these conditions. Additionally, we explore the therapeutic potential of GSH synthesis inducers in mitigating these mitochondrial dysfunctions, as well as their effects on inflammation and the progression of CKD and CRS types 3 and 4.

Graphical abstract

Image 1

Highlights

• Mitochondrial redox imbalances promotes AKI to CKD progression and CRS development.

• Metabolic reprograming and disrupted mitochondrial biogenesis enhances CRS type 3 and 4.

• NAC have shown promise CRS protection associated to AMPK-SIRT1/3-PGC-1α axis.

Keywords

Acute kidney injury
Chronic kidney disease
Cardio-renal syndromes
Mitochondrial dysfunction
Glutathione
Redox signaling
AMPK
SIRT1/3
PGC-1α
==== Body
pmc1 Introduction

The interaction between the heart and the kidney are vital for maintaining systemic homeostasis, but disruptions in this communication can lead to various forms of cardio-renal syndrome (CRS). The mechanisms underlying CRS involve hemodynamic, neurohormonal, and inflammatory factors. CRS was firstly defined and classified by the Acute Dialysis Quality Initiative (ADQI) in 2008 [1]. This classification became complex in clinical practice due to the difficulty in determining the origin and causal relationships, and the presence of shared risk factors, such as diabetes and hypertension [2]. In type-1 CRS, acute heart failure (HF; i.e., decompensated HF or acute myocardial infarction) leads to acute kidney injury (AKI), while in type-2 CRS, chronic HF (i.e., congestive HF) contributes to the development of chronic kidney disease (CKD). More important for this review is type-3 CRS, where AKI (i.e., acute interstitial nephritis, bilateral ureteral obstruction) induces acute HF. On the other hand, in type-4 CRS, a long-term CKD triggers the development or progression of chronic HF [3]. Thus, the reno-cardiac syndromes (types 3 and 4) are characterized by primary renal events, either AKI or CKD, preceding cardiac dysfunction [4].

AKI is characterized by the sudden loss of kidney function and is clinically determined by increased serum creatinine levels [5]. It is associated with a 38 % higher risk of major cardiovascular events (i.e., acute myocardial infarction) and with 86 % elevated cardiovascular mortality [6]. Also, AKI was linked to a more than 50 % increased risk of HF and arrhythmias [7]. The incidence of CRS type 3 has been described in 17–29 % [8,9]. In particular, AKI is present in 2–60 % of the population and can be influenced by various risk factors and clinical conditions [10,11]. In animal models, both HF and rhythm disturbances occurred shortly after AKI due to ischemia/reperfusion (I/R) [12,13]. Interestingly, changes in the metabolomics profile of the heart after AKI-I/R were related to metabolic reprogramming, as occurs after myocardial ischemia [14]. Remarkably, one-third of AKI cases do not fully recover, leading to persistent kidney dysfunction and an increased risk of developing CKD [15]. Indeed, Abdala et al. estimated an odd ratio of 4.31 (95 % CI 3.01–6.17; p < 0.01) for CKD development in AKI patients [16].

In CKD, an intricate bidirectional interaction with the cardiovascular system can damage the kidney and the heart. CKD and HF frequently co-occur, affecting approximately 50 % of patients with either condition [17]. CKD is defined as abnormalities of the structure or function of the kidney, which are maintained for at least three months. Its primary drivers include aging, diabetes, and hypertension [18]. The global prevalence of CKD has increased to 9.1 % [18], which may be responsible for the increased prevalence of type-4 CRS (5.5–76.25 %) [[19], [20], [21]]. End-stage renal disease (ESRD), the most severe form of CKD, is fatal without dialysis or kidney transplantation [22,23]. The pathophysiology of CKD is complex and involves dysregulated molecular mechanisms in the kidney that lead to maladaptive responses. CKD doubles the risk of patients developing HF and coronary heart disease [24]. Also, it triggers a higher risk of atrial fibrillation, ventricular arrhythmias, and sudden cardiac death [25]. CKD patients have a 10-20-fold increased risk of cardiac mortality compared to age- and gender-matched control subjects [26]. In this regard, HF is the leading cause of mortality in CKD patients, and 7.6 % of deaths from CVD were attributable to CKD [18,27].

Mitochondria are now considered vital cellular signaling and metabolism regulators, transcending their well-known function in energy production [28]. In 5/6 nephrectomy-induced CRS 4 models, mitochondrial damage and apoptosis play an essential role in developing cardiac dysfunction [29,30]. Additionally, mitochondria are considered one of the main sites of reactive oxygen species (ROS) production and redox signaling regulation. Mitochondria contain their own distinct pool of glutathione reduced/glutathione disulfide (GSH/GSSG), which maintains the organelle's redox balance and plays a crucial role in regulating key energy metabolic pathways [31]. Several proteins and factors, including those from mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), β-oxidation, Krebs cycle, redox signaling, and sirtuins (SIRT), are sensitive to GSH/GSSG changes leading to mitochondrial alterations [32]. Notably, the disruption of mitochondrial GSH/GSSG homeostasis has been identified as a critical feature of CKD, making interventions that normalize this balance a potential therapeutic target [33].

This review explores the pathophysiological molecular mechanisms underlying metabolic reprogramming in AKI, CKD, and the associated type 3 and 4 CRS, with a focus on glutathione redox signaling and the AMP-activated protein kinase (AMPK) -SIRT1/3- peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis.

On the other hand, N-acetylcysteine (NAC), a thiol-containing antioxidant known to replenish intracellular GSH [34], has shown promise in addressing oxidative stress and mitochondrial dysfunction in renal, cardiac, and cardio-renal diseases [34,35]. We will delve into the current understanding of NAC's role in modulating cellular and mitochondrial GSH/GSSG status, particularly its interaction with SIRT1 and SIRT3, in the context of CKD and CRS. This comprehensive analysis aims to shed light on the potential of NAC as a therapeutic strategy for mitigating oxidative stress, restoring mitochondrial function, and potentially improving outcomes in these complex disease states.

2 Mitochondrial bioenergetics impairment and metabolic reprogramming from AKI to CKD and reno-cardiac diseases

The kidney is the second energy-consuming organ, behind the heart and ahead of the brain, with an estimated metabolic rate of >400 kcal/kg tissue/day [36], mainly used for reabsorption of ions and glucose production. Thus, renal oxygen consumption (VO2) ≈ of 10 ml/min represents two-thirds of the cardiac VO2 and requires approximately 20 % of cardiac output [37,38]. More than 80 % of the renal O2 consumption is attributable to the active transport mechanisms derived from Na+/K+-ATPase activity. Therefore, mitochondrial density through the tubular nephron segments is highly enriched [39]. Fig. 1 illustrates the segment-specific energy production profile in the kidney, with OXPHOS dominating ATP generation in the outer cortex and glycolysis becoming increasingly important in the inner medulla under hypoxic conditions (PO2 10–15 mmHg) [37,38].Fig. 1 Energetic Metabolism Across Nephron Segments and them correspond alteration in AKI and CKD transitions. The figure depicts the variation in energy production pathways along different segments of the nephron. In the renal cortex, characterized by higher oxygen partial pressure (PO2), the proximal tubule (PT), cortical thick ascending limb (CATL), and distal convoluted tubule (DCT) demonstrate higher mitochondrial density and a greater reliance on oxidative phosphorylation (OXPHOS) for ATP production. Conversely, the inner medullary tubular segments predominantly utilize glycolysis, supplemented by metabolites from the proximal tubule. AKI= Acute kidney disease: ATL = ascending thin limb of Henle's loop; CATL = cortical thick ascending limb; CKD = cronic kidney disease; DCT = distal convoluted tubule OXPHOS = oxidative phosphorylation; PO2 = oxygen partial pressure; PT = proximal tubule; ROS = reactive oxygen spices; TDL = thin descending limb of Henle's loops; ΔΨm = mitochondrial membrane potential. Created with BioRender.

Fig. 1

The proximal convoluted tubule (PCT) exhibits a distinct metabolic specialization, relying exclusively on mitochondrial oxidation of preferred substrates (fatty acids, lactic acid, citrate, and glutamate) for energy generation, as it lacks the enzymes necessary for glycolysis (Fig. 1) [39,40]. This agrees with the higher susceptibility of PCT cells to experience mitochondrial membrane potential (ΔΨm) depolarization in pathological situations, which is linked to the ATP synthase's inability to hydrolyze ATP via reverse activity [41,42]. Mitochondrial β-oxidation in the PCT supports both reabsorption and gluconeogenesis. The glucose produced via gluconeogenesis is essential for the metabolically active cells in the medulla. Additionally, lactate generated in the medulla is transported to the PCT and utilized as a substrate in the gluconeogenesis, establishing a metabolic cycle [43]. Therefore, energetic homeostasis in PCT is fundamental for maintaining the medullar nephron segment bioenergetics.

In the heart, one-third of cardiomyocyte volume is occupied by mitochondria, providing up to 95 % of the required ATP, mainly from β-oxidation [44,45]. Interestingly, mitochondrial dysfunction observed in the kidneys during AKI and CKD appears to be mirrored in the heart during CRS, [2,34,46,47]. This suggests a shared pathophysiological mechanism, resulting in cardiac metabolic reprogramming, diminished ATP production from β-oxidation and increasing ROS generation [34,46]. Despite their potential significance for developing novel therapeutic strategies, the precise pathophysiological mechanisms linking mitochondrial impairment to type-3 and -4 CRS remain poorly elucidated [2,46].

In this section, we highlight the early deterioration of mitochondrial components, specifically the electron transport system (ETS) and β-oxidation, alongside the reduction of gluconeogenesis and the increase of glycolytic pathways in the kidney. These alterations are common mechanisms underlying the progression of AKI and CKD. Additionally, we present recent evidence demonstrating a similar metabolic reprogramming in the heart in CRS types 3 and 4.

2.1 Lipid accumulation and reduction of the fatty-acid β-oxidation in reno-cardiac disease

The accumulation of lipids in the kidney and plasma represents a prominent and potentially critical early event in the pathogenesis of CKD, as evidenced by multiple experimental models [[48], [49], [50]]. An early increase in triglyceride synthesis and release of fatty acids persists into the more advanced stages of renal injury [51,52]. Moreover, dyslipidemia affects approximately one-third of patients in the early stages of renal dysfunction [53], with plasma levels of triglycerides, cholesterol, low-density lipoproteins (LDL), and very-low-density lipoproteins (VLDL) increasing as CKD progresses [48,54]. Within the nephron, the proximal tubule and glomerulus are particularly vulnerable to lipid accumulation, which can contribute to the initiation and progression of renal damage [48,55,56]. This vulnerability has been linked with the rise of the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) and the lipid uptake transporters, cluster of differentiation 36 (CD36), and the fatty acid binding protein (FABP) [48,57,58]. Also, key lipogenesis factors, such as the sterol regulatory element-binding protein1 (SREBP1), are overexpressed in patients with CKD [59]. In parallel, the deregulation of CCAAT/enhancer binding protein-α (C/EBP-α), a transcription factor that interacts with PPAR-γ in lipogenesis, promotes lipid accumulation and renal fibrosis [60]. Notably, renal fatty acid accumulation activates macrophage infiltration and pro-fibrotic pathways (i.e., TGF-β) [61,62]. Indeed, overexpression of CD36 in mice induced metabolic reprogramming characterized by enhanced fatty acid β-oxidation and epithelial-mesenchymal transition, ultimately promoting the development of CKD [55].

Intriguingly, renal lipid accumulation has been attributed to reduced β-oxidation, ETS, and OXPHOS [55,61,63,64]. In experimental models of renal mass reduction, obstruction, and cytotoxicity, the decreased activity and expression of β-oxidation enzymes precede the overproduction of reactive oxygen species (ROS) and subsequent pro-inflammatory and profibrotic processes [55,61,63,64]. This downregulation of β-oxidation enzymes predominantly affects the proximal tubular and glomerular segments [49,61,65], correlating with an early decline in complex I (CI) activity and mitochondrial uncoupling, further increasing ROS production [61,63,64]. Additionally, this decreased β-oxidation has been linked impaired mitochondrial biogenesis, mediated by the PGC-1α/AMPK signaling pathway in animal models [63,64,66] and patients [67]. This response perpetuates lipid accumulation and further diminishes mitochondrial β-oxidation, establishing a vicious circle that favors metabolic reprogramming.

Likewise, heart function depends primarily on mitochondria β-oxidation [68]. In cases where the demand for ATP is high, glycolysis enhancers can compensate the β-oxidation However, the lack of flexibility between these energy sources leads to reduced cardiac efficiency and impaired contractility [69]. CKD can induce functional and structural cardiac abnormalities, characteristic of heart failure [21]. In heart failure, the heart modifies its energy substrate utilization as a compensatory mechanism, which ultimately culminates in pathological cardiac remodeling [70]. Interestingly, a recently published study observed that the development of type 4 CRS in a UUO model was markedly characterized by the downregulation of genes related to oxidative mitochondrial β-oxidation [71]. Another study showed that CKD promotes high phosphate concentrations in myocardial mitochondria and decreases OXPHOS and FA metabolism. These effects were attributed to the downregulation of PGC-1α in an interferon regulatory factor 1 (IRF1)-dependent manner [72]. Notably, there is a paucity of research investigating the specific molecular alterations driving cardiac pathology during fatty-acid β-oxidation in the context of type 3 and 4 CRS. A deeper understanding of this metabolic pathway in these conditions is crucial for developing targeted therapeutic interventions.

2.2 Alterations of the Krebs cycle and OXPHOS

The loss of functional nephrons during CKD induces higher solute reabsorption and hemodynamic changes in the remaining nephrons. This promotes increased metabolic rates and ATP consumption in the tubular segments [61,73]. Likewise, oxidative stress and inflammation decrease O2 supply and induce mitochondrial decoupling [61,64,74], reducing ATP production [75,76]. Consequently, mitochondria in the renal cortex cannot meet the increased ATP demand [61,64,77]. Due to alterations in the Krebs cycle and ETS, primarily in the proximal tubule, ATP levels decrease by 25 %–70 % in AKI and CKD, respectively [61,64,77].

The Krebs cycle intermediates are strongly affected in AKI and CKD, as evidenced by the alteration of related enzymes and metabolites [[78], [79], [80]] (Fig. 2A). Dynamic regulation, release and excretion of these factors may depend on kidney damage injury. Citrate accumulation is observed in obstructive and ischemic models in parallel to a decline in renal aconitase activity [61,79,[81], [82], [83]]. Increased urinary excretion of α-ketoglutarate (α-KG) is consistent with the reduction in renal isocitrate dehydrogenase-3 in CKD patients, which results in lower concentration of α-KG in blood serum [79,84,85]. Similarly, alterations in succinyl-CoA or succinate dehydrogenase (SDH, also named mitochondrial complex II, CII) were associated with decreased levels of urine and renal succinate in CKD patients [86]. However, as a compensatory mechanism, succinate can be stimulated by increased activity of SDH [81,82,87]. Thus, succinate metabolism is a significant area of research in the context of CRS.Fig. 2 Metabolic Reprogramming in Kidney and Heart Disease. A) AKI to CKD Transition. Mitochondrial dysfunction, evident from early AKI to CKD progression, is characterized by decreased TCA cycle, β-oxidation, and ETS activity. This leads to a drop in mitochondrial membrane potential (ΔΨm), ATP production, and increased reactive oxygen species (ROS) generation. Consequently, gluconeogenesis, anaplerotic reactions, and glutamate release by the proximal tubule are inhibited. β-oxidation inhibition increases lipogenesis factors and intracellular lipid accumulation. Elevated mitochondrial ROS favors damage-associated molecular patterns (DAMPs) accumulation and angiotensin II (Ang II) activation, enhancing the hypoxia-inducible factor 1-alpha (HIF-1α) pathway and inhibiting peroxisome proliferator-activated receptor alpha (PPARα)/Forkhead box O1 (FOXO1). This increases glycolysis and extracellular vesicle (EV) secretion, contributing to metabolic reprogramming in distal segments through EV action on receptor cells. B) Cardiomyocytes Reprogramming in Cardiorenal Syndrome (CRS). In CRS types 3 and 4, pathological processes stemming from renal impairment (pressure overload, oxidative stress, increased cardio-renal connectors) induce HIF-1α pathway activation in the heart. This, coupled with reduced mitochondrial biogenesis and Krebs cycle regulators (e.g., pyruvate kinase M1 [PKM1]), leads to decreased ETS activity and mitochondrial OXPHOS. Reduced OXPHOS increases glycolytic pathways (e.g., estrogen-related receptor gamma [ERRγ] and Hippo/Yes-associated protein 1 [YAP1]), enhancing glucose utilization.

ACO: aconitase; Ang II: angiotensin II pathway, ANT: adenine nucleotide translocator; αKDH: alpha-ketoglutarate dehydrogenase; CI: complex I, CIII: complex III; CIV: complex IV; CD36: cluster of differentiation 36; CPT1: Carnitine palmitoyl transferase; DAMPs: damage-associated molecular patterns; EVs: extracellular vesicles; FABP1: fatty acid-binding protein 1; FOXO1: forkhead box protein O1; Glu: glucose; GLUT 1 = glucose transporter 1,I DH: isocitrate dehydrogenase; MDH: malate dehydrogenase; NF-κB: nuclear factor kappa B; PKM1 = pyruvate kinase muscle isozyme 1, PPAR-α/γ: peroxisome proliferator-activated receptor alpha/gamma; ROS: reactive oxygen spices; SREBP1: sterol regulatory element binding protein 1; TCA: tricarboxylic acid cycle; TGF-β: transforming growth factor-beta; V/LDL = very/low-density lipoprotein; YAP1= Yes-associated protein 1; ΔΨm = mitochondrial membrane potential. Figure created usingBioRender.com.

Fig. 2

Accumulation of succinate in kidney could induce its release to the circulation [88]. There is no solid evidence related to alterations of succinate in serum from AKI patients, but after experimental I/R-induced AKI, succinate was also increased in kidney and plasma [82,87]. In the proximal tubule, succinate alters respiration and stimulates membrane hyperpolarization by increasing K+ uptake [89,90]. It also promotes arachidonic acid, prostaglandin -E2 and -I2 discharge, which favors renin release [90,91]. Succinate inhibits 2-oxoglutarate dehydrogenase (2OGDH) and stabilize the hypoxia-inducible factor-1 α (HIF-1α) [92]. HIF-1α improves eGFR but acts as a pro-inflammatory signal promoting the expression of IL-1β in macrophages [92]. Therefore, succinate participates in the inflammatory response of kidney diseases. In fact, plasma succinate correlated negatively with eGFR in CKD patients [93]. In this context, succinate may play a multifaceted role in managing HF. Targeting metabolism of the mitochondrial succinate has emerged as a promising strategy to prevent I/R injury. Malonate, a competitive inhibitor of SDH, can reduce infarct size in models of acute myocardial infarction by this preventing ROS production by at mitochondrial complex I [93]. Also, reducing SDH partially reversed metabolic reprogramming and promoted adult cardiomyocyte regeneration [93]. However, succinate may exacerbate mitochondrial dysfunction by enhancing mitochondrial fission and cardiomyocyte apoptosis. Succinate accumulation was also linked to cardiac hypertrophy [94], and may trigger metabolic remodeling and epigenetic changes that alter myocardial gene expression toward imbalanced FAO/glycolysis [95]. The interplay between CKD, HF, and succinate metabolism warrants further exploration. In general, reduction in the Krebs cycle activity has been attributable to oxidative stress and downregulation of mitochondrial regulators [[78], [79], [80]].

Additionally, a reduction in mitochondrial ETS activity appears to be a common pathological mechanism in animals and patients with CKD [55,66,67]. The CI activity decreased as early as the first day in animal models of renal mass reduction or cytotoxicity [35,96,97]. Obstructive models exhibited a similar decrease in CI activity but at later time points [63,83]. As is shown in Fig. 2 A, the increased susceptibility of CI to renal injury is closely linked to the rapid development of oxidative stress [35,65,96,98] and the irreversible oxidation of redox-susceptible free cysteines at this complex [99]. Additionally, the activities of complex III (CIII) and complex IV (CIV) decreased throughout the first month of injury [35,83,96,97]. CII activity is also diminished in models of ischemia, renal obstruction, and nephrectomy [65,83,100,101]. However, a slight increase in CII-linked respiration was detected in early stages of nephrectomy and age-related models [102,103], suggesting a compensatory mechanism for the drastic decrease of CI [65,102]. Finally, ATP synthase activity is also reduced in AKI and in CKD [35,96,97]. This response reduces mitochondrial ATP production, particularly in cortical segments, due to mitochondrial uncoupling and lower mitochondrial mass [35,63,64,96].

Oxidative stress in the heart is produced during AKI. Thus, the association of oxidative stress and mitochondrial disturbances closely produces cardiac pathology. In this sense, it has been demonstrated that OXPHOS and membrane potential are initially affected by disturbances in CI activity and GSH depletion [104]. Other stressors in AKI, such as hemodynamic impairment may also trigger endoplasmic reticulum stress activating metabolic reprogramming and both protective and detrimental pathways like X-box binding protein 1 and the inositol-requiring enzyme 1α [105].

Most of the heart's ATP is produced through OXPHOS in the mitochondria. However, during HF or cardiac remodeling, OXPHOS is significantly affected by mitochondrial impairment [70]. HF is a common complication of CKD, often induced by pressure overload [21]. In HF, metabolic modifications can occur, affecting the oxidative capacity of mitochondria in an estrogen-related receptor γ (ERRγ) dependent manner. In adenine-induced CKD, the capacity of OXPHOS in cardiac muscle was reduced by 30 %. These alterations were associated with the oxidation of the redox potential and a modest decrease of ΔΨm, potentially explained by the reduced activity of the alpha-ketoglutarate dehydrogenase (αKGDH) and CIV [106]. Few studies have investigated cardiac mitochondria in CRS type III and IV. However, CKD has been shown to impair skeletal muscle mitochondrial function, as evidenced by decreased respiratory control index and increased hydrogen peroxide (H2O2) production [107]. Our group reported a similar decrease in the respiratory control index in CI and CII-linked respiration in cardiac mitochondria in 5/6 nephrectomy-induced CRS type IV [108]. Similarly, folic acid-induced CRS type III is also associated with decreased CI and CII activity, reducing cardiac mitochondria ATP production [34]. As shown in Fig. 2B, early alteration in the cardiac OXPHOS system has been linked to the promotion of CRS type III and IV. It is important to note that further research is needed to fully understand the cardiac profile and its association with alterations in OXPHOS in the pathological pathways that trigger CRS development.

2.3 Modification of glycolysis and gluconeogenesis

Under normal conditions, glycolytic ATP production is predominant in endothelial cells from distal segments and mesangial cells, but not in S1 and S2 proximal tubules [39,109]. In the renal cortex, PO2 and OXPHOS are higher than in the deeper medulla, where PO2 is low, and glycolysis is the main source of ATP [39,110,111]. However, cells in the thick ascending limb of Henle and other distal tubule segments can switch from OXPHOS to glycolysis when faced with PO2 reduction, making them less sensitive to hypoxia [109,112,113]. After renal injury, the reduction of β-oxidation in the proximal tubule is accompanied by glycolysis activation [62], which may be an early adaptation to maintain energy balance and tissue regeneration. However, it's important to note that enhanced glycolysis, while initially beneficial, is insufficient to maintain ATP levels over time, and its prevalence can promote pro-inflammatory and -fibrotic responses [56,114,115]. Moreover, glycolytic metabolism increases renal fibroblast proliferation and the production of TGF-β, fibronectin, and alpha-smooth muscle actin (α-SMA) [116,117]. In fact, renal biopsies from CKD patients have shown an increase in glycolytic enzymes and inflammation markers [115]. In experimental AKI and CKD, inhibiting glycolytic enzymes or glucose transporters reduced renal lactate and acid uric levels, along with apoptosis, inflammation, and fibrosis [[118], [119], [120]].

Furthermore, the increase of glycolytic pathways has also been related to the activation of the HIF-1α [121]. Early renal hypoxia is induced by hemodynamic changes, including increased renal resistance, damage to blood vessels, decreased nitric oxide (NO), and increased oxygen consumption by immune and proximal tubule cells [36,121,122]. Renal hypoxia then induces prolyl hydroxylase inactivation and HIF-1α stabilization. Additionally, the pro-oxidative environment favors HIF-1α production through NF-kB- and angiotensin II/PI3K/PKC-dependent mechanisms [[123], [124], [125]]. In turn, HIF-1α increases glucose flux by upregulating the expression of glycolytic enzymes and transporters. Conversely, HIF-1α decreases ETS activity, mitochondrial biogenesis and induces mitochondrial degradation [121,126]. Interestingly, in CKD, HIF-1α also stimulates the production of extracellular vesicles (EVs) from renal cells, which are exported to distal cells potentially for metabolic reprogramming [98,127,128]. The content of these EVs can be modified by hypoxia, enriching their cargo with glycolytic enzymes and microRNAs (miRNAs) [129,130]. This response has also been implicated in diabetic nephropathy (DN) development under high glucose conditions [131]. Similarly, in ischemia/reperfusion and obstructive-induced CKD, the HIF-1α-stimulated EVs from tubular epithelial cells stimulate metabolic reprogramming and the production of inflammatory cytokines production in renal macrophages and distal tubule cells [132,133]. Thus, HIF-1α may extend metabolic reprogramming from proximal to distal segments.

In addition, renal gluconeogenesis takes place exclusively in the proximal tubule, where lactate, glutamine and glycerol are used as substrates instead of hexoses or other carbohydrates [[134], [135], [136]]. Lactate is responsible for half of glucose production and is principally taken up at the apical membrane of S2 and S3 segments by monocarboxylate transporters 1 and 2 [137,138]. Despite this, glucose production in the kidney is the second highest (after the liver) with a renal net balance of 1 mmol/kg/min [43,136]. However, the kidney is both a glucose producer (in the cortex) and a consumer (in the medulla). The distal tubule, thick ascending limb of Henle, convoluted tubules, and collecting ducts can receive glucose from the proximal tubule. These segments produce lactate, which returns to the cortex to enter into the gluconeogenic pathway, establishing a cortical-medullary recycling loop [43,136,139]. Furthermore, gluconeogenesis is important for anaplerotic reactions that restore Krebs cycle intermediates and, thereby, subsequent mitochondrial function [40,138,140]. In this regard, changes in gluconeogenesis have been observed in patients with AKI and during the progression to CKD. Renal biopsies have unveiled reduced levels of gluconeogenic enzymes alongside disruptions in glucose production and lactate clearance in the proximal tubules from the early stages of injury. In proteinuria-, ischemic-, and obstructive-CKD models, the downregulation of PPARα, HNF4a and FOXO1 decreased gluconeogenic enzymes in the proximal tubule, which was related to an increase in TGF-β and kidney fibrosis, thereby increasing the mortality rate [141,142]. These responses were associated with a lowering of PGC1-α and an increase in HIF-1α in both AKI and CKD models [56,[78], [79], [80],114,115,121]. Thus, the switches in metabolic reprogramming induce a direct reduction in gluconeogenesis and an indirectly reduction by lowering the ATP production by OXPHOS.

In physiological conditions, the heart relies minimally on glucose for energy metabolism [143]. However, in pathological conditions, the increase in energy demands is met by enhanced aerobic metabolism Fig. 2 B. This metabolic flexibility initially allows the heart to maintain ATP production even in low oxygen conditions [144]. When oxygen delivery is compromised, transcription factors like HIF-1α are upregulated to conserve oxygen by supressing mitochondrial function, while simultaneously stimulating glucose uptake and glycolysis [145]. In compensatory cardiac hypertrophy a response to acute pressure elevation, as seen in CKD, the interaction of nuclear effectors (such as through the Hippo pathway) mediates GLUT1 gene upregulation [146]. Furthermore, elevated glucose utilization strongly predicts cardiac hypertrophic and hemodynamic stress [147]. Accordingly, due to pressure overload, reduced expression of pyruvate kinase muscle isozyme (PKM1) exacerbates cardiac fibrosis and dysfunction in the failing heart. This is associated with lower heart mitochondrial respiration and ATP production [147]. On the other hand, studies using empagliflozin (an antihyperglycemic drug) have shown that shifting energy substrate utilization from glucose to the ketone bodies, FA and branched-chain amino acids increases ATP content and myocardial work efficiency, ultimately improving cardiac function and structure [147]. Together, these studies suggest that the modification from OXPHOS to glycolytic metabolism during reno-cardiac pathology contributes to heart function loss and pathology development.

3 Role of GSH in the mitochondrial alterations from AKI to CKD and reno-cardiac disease

AKI and CKD are characterized by oxidative stress [148,149], with nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), mitochondrial ETS, and Krebs cycle dehydrogenases being the main ROS sources [98,116,148]. Mitochondria, peroxisomes, and the endoplasmic reticulum (ER) also produce ROS at lower concentrations as part of their normal metabolism, which act as second messengers in several pathways [150,151]. For example, intracellular fluctuations of H2O2 (1–100 nM) induce changes in cell metabolism, a phenomenon known as “oxidative eustress” [99,152]. In contrast, in “oxidative distress,” higher H2O2 levels (>100 nM to μM) promote unspecific oxidation of biomolecules, cell damage, and death [152,153]. Therefore, ROS must be maintained in “the redox tone”, which varies widely between cell compartments [152,153]. For example, in the cytosol, the H2O2 concentration is 80 nM, compared to 5–20 nM in the mitochondrial matrix, and 700 nM in the ER lumen [154,155].

As is shown in Fig. 3, the redox tone mediates H2O2-dependent cell signaling by changes in the GSH/GSSG, inducing protein modification, especially in Cys [156,157]. Cys represent only 2 % of total amino acids but are the most conserved in peptide sequences [149], frequently found in the catalytic core, chelating transition metal centers, and protein surface [99,158]. Interestingly, mitochondria are the most free Cys-enriched organelles (60–90 mM of thiol residues) [159], which regulates factors involved in energy metabolism (see Fig. 3) and biogenesis [31,99,160].Fig. 3 Glutathione-H2O2 Signaling in Energy Metabolism and Redox Tone Regulation. H2O2 and glutathione (GSH) levels are tightly regulated across cellular compartments. The endoplasmic reticulum (ER) maintains a predominantly oxidative environment due to protein disulfide isomerase (PDI)/ER oxidoreductin 1 (ERO) activity and a low GSH/GSSG ratio. In contrast, the mitochondrial matrix exhibits a reduced redox tone due to a high GSH/GSSG ratio and low H2O2 levels. An increase in mitochondrial H2O2 concentration and a decrease in the GSH/GSSG ratio triggers glutaredoxin 2 (GRX2) —mediated S-glutathionylation of mitochondrial matrix proteins. This partially inhibits the electron transport system (ETS), TCA cycle, and β-oxidation pathways, reducing oxidative phosphorylation (OXPHOS) and ROS production while increasing mitochondrial antioxidant defenses to preserve homeostasis. Once mitochondrial H2O2 levels decrease and NADPH levels increase, GRX2 removes the protein S-glutathionylation modifications, restoring pathway flows. S-glutathionylation in the cytosol stimulates the pentose phosphate pathway (PPP), increasing the NADPH/NADP + ratio. AQ8 = aquaporin 8; CI = complex I, CII = complex II, CIII = complex III; CIV = complex IV; EGSH/GSSG = glutathione redox potential; ETS = electron transport system; ERO = endoplasmic reticulum oxidoreductin 1; GSH = reduced glutathione; GSHT = total glutathione, GSSG = oxidized glutathione; GRX1/2 = glutaredoxins 1/2; H2O2 = hydrogen peroxide; IMDSB = intermolecular disulfide bridge; NOX4 = NADPH oxidase 4; OXPHOS = oxidative phosphorylation; ROS = reactive oxygen spices; SOD = superoxide dismutase; PDI = protein disulfide isomerase; PPP = penthouse phosphate pathway; TCA = tricarboxylic acid cycle; UCP = uncoupled protein; VDAC = voltage depending anion channel. Figure created usingBioRender.com.

Fig. 3

3.1 The GSH/GSSG ratio at mitochondria

The tripeptide GSH is the most abundant low-molecular weight antioxidant in cells, reaching intracellular concentrations of 0.5–30 mM and extracellular concentrations of 2–20 μM [161,162]. GSH is ionized at physiological pH, necessitating specific transporters and generating varying GSH concentrations between organelles [161,163]. Free GSH is in equilibrium with its oxidized form, GSSG. Therefore, the GSH/GSSG ratio can be an indicator of redox state, defined by the glutathione redox potential (EGSH/GSSG) [163]. The cytosol has a high GSH/GSSG ratio (10–50) and total concentrations ranging from 10 to 30 mM [163,164]. Mitochondria display independent GSH redox states, import systems, glutathione-utilizing enzymes, and a mechanism of GSSG reduction between the matrix and the intermembrane space (IMS). In the IMS, the GSH/GSSG ratio is similar to that of the cytosol, while it is more reduced in the matrix (GSH concentration: 10–14 mM) [165,166]. Because mitochondrial compartments lack the enzymes to synthesize GSH de novo, it must be imported from the cytosol. As is shown in Fig. 3, a mitochondrial pore called the voltage-dependent anion channel (VDAC) and the translocase of the outer membrane (TOM) are associated with GSH transport through the outer mitochondrial membrane (OMM) [163,167]. Meanwhile, GSH transport in the inner mitochondrial membrane (IMM) is mediated by the oxoglutarate (OGC) and the dicarboxylate (DIC) carriers [168]. In contrast, mitochondria export GSH through the IMM is mediated by the ABC transporter of mitochondria 1 (ATM1), by the extrusion of GSSG or glutathione adducts [169]. Both compartments possess their own GSSG reduction system. The glutathione reductase (GR) is localized in both IMS-cytosol and mitochondrial matrix [170]. However, glucose 6-phosphate dehydrogenase (G6PDH) is find in cytosol but not in the matrix. Conversely, NADPH is generated in the matrix by the malic enzyme, the methylene tetrahydrofolate dehydrogenase (MTHFD2), and the nicotinamide nucleotide transhydrogenase (NNT) [[171], [172], [173]]. The NNT enzyme uses the ΔΨm to reduce NADPH from NADH equivalents [173,174]. Notably, the highest NNT expression is in the heart and kidneys (i.e., tubular epithelial cells) [174].

3.2 The GSH metabolism at the kidney

Most de novo GSH synthesis occurs in the liver [175]. However, GSH synthesis also occurs in the kidney, in a two-step pathway (Fig. 4A), with the first step catalyzed by the glutamate cysteine ligase (GCL) and the second by the glutathione synthetase (GS) [162]. The GCL catalyzes the rate-limiting step in GSH biosynthesis and is composed of a heavy catalytic subunit (GCLC) of 73 kDa and a regulatory subunit (GCLM) of 31 kDa. The catalytic subunit is inhibited by GSH in a feedback regulation mechanism and allosterically activated by the heterodimeric formation with GCLM [176,177]. The activity of GCL is post-transcriptionally regulated by phosphorylation and glycation [178,179]. At the transcriptional level, ROS and other electrophiles triggers GCLC and GCLM expression through the nuclear factor erythroid 2-related factor (Nrf2), the mitogen-activated protein kinase (MAPK), and the musculoaponeurotic fibrosarcoma (MAF) families dependent pathways [[180], [181], [182], [183]]. Additionally, inflammatory signals like the IKKβ–NF–κB pathway regulate GCLC/GCLM [184]. On the other hand, GS is a homodimer, only controlled by transcriptional expression [162,185].Fig. 4 Glutathione Metabolism in Renal Cells and Cardiomyocytes. A) Glutathione Metabolism in Renal Cells. GSH is imported into renal cells via organic anion transporters (OAT1/2) and NaC3. In the cytosol, detoxification systems utilize GSH, generating oxidized glutathione (GSSG) or conjugating it with xenobiotics (X). GSSG is reduced back to GSH in a glutathione reductase (GR)/NADPH-dependent manner or exported by extrusion systems. Extracellular proteases can then release cysteine (Cys) from exported GSH conjugates. GSH import into mitochondria involves passage through the outer mitochondrial membrane (OMM) mediated by voltage-dependent anion channels (VDAC)/translocase of the outer membrane (TOM) and through the inner mitochondrial membrane (IMM) mediated by the dicarboxylate carrier (DIC)/oxoglutarate carrier (OGC). GSSG reduction in the mitochondrial matrix is linked to nicotinamide nucleotide transhydrogenase (NNT), malic enzyme, and methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). B) Glutathione Metabolism in Cardiomyocytes during Heart Damage. In healthy cardiomyocytes, GSH levels are maintained by the extrusion of GS-X adducts by multidrug resistance-associated protein 1 (MRP1) and by the reduction of GSSG in a GR/NADPH-dependent manner. De novo GSH synthesis is supported by the import of Cys, glutamate (Glu), and glycine (Gly) from the extracellular medium. Under pathological damage, the GSH/GSSG ratio and the GSH-dependent antioxidant system decrease significantly. This induces the activation of the PERK/eIF2α/ATF4 pathway, favoring the induction of Chac1/2-OPLAH-CGDP2, which triggers intracellular GSH decomposition.

ARE = antioxidant response element; ATF4= Activating transcription factor 4; ATM1 = ABC transporter of mitochondria 1; DP dipeptidase; GCL = glutamate cysteine ligase; GGDP2= Cys-Gly dipeptidase 2; GCLC = heavy catalytic subunit of GCL; GCLM = regulatory subunit of GCL; GGT = γ-glutamyl transferase; GPx = glutathione peroxidase; GR = glutathione reductase; GS = glutathione synthase; GSH = reduced glutathione; GSHT = total glutathione, GSSG = oxidized glutathione; GST = glutathione S- transferase; GS-X = glutathione adduct with xenobiotic; eIF2α = eukaryotic translation initiation factor 2 subunit alpha,H2O2 = hydrogen peroxide; IMS = intermembrane space; IMM = inner mitochondrial membrane; MAPK = Mitogen-activated protein kinases; MRP1 = multidrug resistance-associated protein 1, MRP2/4 = multidrug resistance-associated protein 2/4; MTHFD2 = methylene tetrahydrofolate dehydrogenase; NaC3 = sodium/carboxylate cotransporter 3; NNT = nicotinamide nucleotide transhydrogenase; Nrf2 = nuclear factor erythroid 2–related factor 2; OAT1/3 = organic anion transporters 1 and 3; OMM = outer mitochondrial membrane; OPLAH = 5-oxoprolinase, RLIP76= RalA-binding protein 1; ROS = reactive oxygen spices; SOD = superoxide dismutase; PERK= PKR-like ER kinase; PP = penthouse phosphate pathway; OGC = oxoglutarate carrier; TOM = translocase of the outer membrane; VDAC = voltage depending anion channel, 2OG = 2-oxoglutarate; 5-OP = 5-oxoprolina, ΔΨm = mitochondrial membrane potential. Figure created using BioRender.com.

Fig. 4

In the kidneys, renal filtration and reabsorption remove 80 % of GSH plasma levels, especially in the proximal tubule [186]. Approximately 50 % of this extraction is mediated by the sodium/carboxylate cotransporter 3 (NaC3) and by organic anion transporters 1 and 3 (OAT1/3) [187]. The kidney also possesses the highest levels of γ-glutamyl transferase (GGT), an enzyme that initiates the extracellular catabolism of GSH- adducts [163,188]. GGT is ocated on the plasma luminal membrane (Fig. 4 A), where it hydrolyses GSH into glutamic acid and cysteinyl-glycine, which is cleaved by cell surface dipeptidases, releasing Cys [188]. Then, Cys is reabsorbed by Cys-related transporter “rBAT-b(0,+)AT” [189]. Meanwhile, multidrug resistance-associated protein 2/4 (MRP) is in charge of the renal efflux of a wide range of GS adducts [163,190,191].

In line with the idea of a greater need for ROS control mechanisms in mitochondria-rich segments [40,112,113], the cortex needs a higher GSH synthesis capacity. Consequently, GSH concentration is highest in the renal cortex and progressively decreases towards the medulla [184]. Furthermore, the GSH/GSSG ratio, GSH import systems, glutathione-utilizing antioxidant enzymes, GS-adducts extrusion systems, and mechanism of GSSG reduction are higher in cortical segments than in the outer medulla and the lowest in the inner medulla [174,187,188,192,193].

3.3 The GSH metabolism at the heart

Similar to the kidney, the high energy demand of the heart makes cardiomyocytes extremely dependent on mitochondrial oxidative metabolism [194,195], favoring the continuous production of ROS. However, under physiological conditions, the intracellular GSH levels, the activity of GSH-dependent antioxidant enzymes, and the capacity of GS-adducts extrusion systems have been reported to be lower than in other tissues [[196], [197], [198], [199]]. The GSH/GSSG ratio maintenance in the cardiomyocyte mainly depends on two mechanisms (Fig. 4 B). The first one is based on preventing GS-adducts accumulation by MRP1-dependent extrusion, which are later cleaved in the extracellular medium to release Gly and Glu, which are reabsorbed into the cell to support GSH synthesis [198,200,201]. In the second mechanism, GSSG or adducts are intracellularly reduced to GSH by the GR-PPP dependent pathway [200,202]. Meanwhile, IMM transport is also regulated by OGC and the DIC carriers, which are highly expressed in the myocardial tissue [203].

Additionally, a new intracellular heart GSH degradation pathway has been recently proposed. As shown in Fig. 4 B, GSH is intracellular degraded by the cytoplasmic glutathione specific γ-glutamyl cyclotransferases 1 and 2 (Chac1/2), releasing 5-oxoproline and Cys-Gly. Both products are later cleaved by 5-oxoprolinase (OPLAH), and Cys-Gly dipeptidase 2 (CGDP2) respectively, thereby releasing the components for GSH synthesis [204,205]. Because Chac1/2, are specific for GSH, an increase in their activities triggers GSH/GSSG reduction, oxidative stress and increases in calcium cytosol levels, thereby favoring heart failure [206]. Furthermore, Chac1 knockdown reduces ferroptosis and cell injury in cardiomyocytes [207]. Additionally, the heart GSH redox homeostasis is easily disrupted under pathological conditions, making cardiomyocytes especially susceptible to oxidative stress [198]. Several studies showed that pathological damages to the myocardium is associated with an early reduction in GSH synthesis, GS-adducts extrusion and GSSG reduction systems [202,208,209], leading to a lower GSH/GSSG ratio and limiting antioxidant enzyme capacity [34,200]. Furthermore, GSH depletion and GPX4 activity reduction are key points in promoting cell death mechanisms in cardiomyocytes, particularly ferroptosis [200,210]. Therefore, understanding heart GSH regulation systems and how to restore redox balance has gained importance in the development of new therapies to prevent myocardial injury [200].

3.4 NAC in mitochondrial GSH alterations and mitochondrial target antioxidants in AKI, CKD and reno-cardiac disease

AKI and CKD exhibit cytosolic and mitochondrial GSH/GSSG ratio reduction in proximal tubule cells from early injury in several models [35,61,83,96,97,211]. Although information on CRS syndrome remains limited, recent studies revealed decreased GSH/GSSG ratios and increased pro-oxidant states in cardiomyocytes and cardiac mitochondria, potentially contributing to heart damage [34,108,212]. The GSH/GSSG ratio reduction stimulates the S-glutathionylation (RS-SG) removal activity of mitochondrial glutaredoxin 2 (Grx2), favoring renal damage [35]. Enzymatic RS-SG protects proteins from the irreversible oxidation of Cys residues under oxidative stress [99,160]. Furthermore, it triggers three processes to recover redox balance: First, the reduction in the activities of the Krebs cycle, ETS, and β- β-oxidation. Second, the reduction of ROS production by these pathways. Third, the pentose phosphate pathway is increased, supporting NADPH and GSH/GSSG ratio restoration [34,35,99,160,213].

In this regard, GSH synthesis inducers have recently been studied to preserve mitochondrial homeostasis and RS-SG levels [35,61,[214], [215], [216], [217], [218]]. Among them, NAC is widely used in experimental models and clinical studies, where it positively affects renal function in AKI and CKD [[214], [215], [216], [217], [218]] and the heart in CRS syndrome [34,[219], [220], [221]]. Furthermore, NAC is perfect for replenishing GSH levels under GSH deficiency conditions, without changing the GSH levels under normal conditions [176,222] and has been proposed as a RS-SG regulator [34,35,61,222]. In AKI and CKD progression, NAC administration reduces renal damage markers [35,61,223,224]. These protective effects have been related to glomerulus [223] and proximal tubule preservation [35,61,225], conservation of renal hemodynamics [35,61,223,226], and ROS and angiotensin II (Ang II) levels reduction [35,61,216,[227], [228], [229]]. Meanwhile, in CRS, NAC administration has shown similar effects, restoring GSH levels, GSH/GSSG ratio, blood flow, and the activity of antioxidant enzymes, and reducing inflammation and mitochondrial ROS production in the heart [34,220,221]. Interestingly, the protective effects are also linked to the preservation of RS-SG levels, and CI and CIII activity by mitochondrial GSH/GSSG ratio restoration in kidney and heart [34,35,61,[230], [231], [232]]. NAC also decreases apoptotic induction, the release of mitochondrial damage-associated molecular patterns (DAMPs), and the activation of the nucleotide-binding oligomerization domain-like receptors (NLR)-family pyrin domain containing 3 (NLRP3) inflammasome and the NF-κB pathways [228,233,234]. Consequently, NAC reduces the pro-inflammatory cytokines release [221,232,[235], [236], [237]] and positively regulates the composition and release of EVs [238], mechanisms associated with mitochondrial regulation.

In AKI, CKD and CRS mitochondrial dysfunction, specifically excessive mitochondrial ROS overproduction and fission induction lead to apoptosis and tissue damage [34,35,65,96,239]. Therefore, antioxidants compounds that target these organelles in a specific form have been developed to prevent this mitochondrial damage. For example, the mitochondrial-targeted coenzyme Q10 (MitoQ) has an antioxidant capacity that depends on ΔΨm induced localization. It reduces mitochondrial ROS and restores ATP levels in preclinical AKI models [240,241], and during nephrotoxicity [242]. The effect is mediated by stimulating sirtuin 3 (SIRT3) activity and reducing cell apoptosis [241]. It is important to note that MitoQ effects have also been detrimental in proximal tubule cells. For example, it induces mitochondrial swelling and depolarization independently of oxygen consumption rate [243]. Thus, the adverse impact of MitoQ has been not related to its antioxidant activity. Instead, it has been associated to its capacity to induce ΔΨm depolarization due to the insertion of an alkyl chain [243].

Like wise, MitoTEMPO is other mitochondria-targeted nitroxide whose activity mimics to the SOD enzyme. In cancer, MitoTEMPO inhibits glycolysis by reducing ROS production [244]. In CKD, MitoTEMPO attenuates renal injury by preserving mitochondrial function and decreasing mitochondrial ROS production [245]. On the other hand, elampretid (also called MTP-131) is a mitochondrial-targeted peptide that binds to cardiolipin and replenishes mitochondrial function. It targets and concentrates in the IMM, where several enzymes produce ROS. In addition, this peptide scavenges ROS and prevents mitochondrial permeability transition pore opening and cytochrome C release. Also, it has been widely used for treating cardiac and renal diseases [245]. It has been reported that MitoTEMPO can decrease mitochondrial superoxide production in the heart and the kidney during diabetic kidney disease by regulating cardiolipin remodeling [246]. In addition, during heart failure with reduced ejection fraction, elampretide favored left ventricular volumes without having adverse effects [247]. However, mitochondrial bioenergetics in the heart was not evaluated in this condition. Interestingly, in another study, elampretide reduced the expression of TGF-β1, NOX4, and the activation of p38 MAPK pathway, probing its protective antioxidant effect against high glucose-induced renal injury [240]. During atherosclerotic renal artery stenosis in patients, elampretide improved renal function, oxygenation, and renal blood flow [248]. This component has not had controversial findings.

Visomitin (SKQ1) compounds are mitochondria-penetrating positively charged cations whose primary function is inhibiting mitochondrial ROS. Like MitoTEMPO, SKQ1 inhibits cell damage triggered by H2O2 [249]. In addition, this compound reverses the downregulation of the antioxidant defense and enzymes. In AKI, this antioxidant improves renal morphology by inhibiting ferroptosis and mitochondrial dysfunction [250]. Furthermore, SKQ1 has been shown to be protective in cardiac hypertrophy by improving antioxidant defense and regulating mitochondrial H2O2 levels [251]. Many other antioxidants not direct directed to mitochondria have been also proven to be efficient in reduce AKI and CKD induced mitochondrial impairment [35,65,83,252,253]. These effects are associated with decreased ROS, increasing OXPHOS capacity and apoptosis reduction. Between them found sulphoraphane, NAC, resveratrol, curcumin, quercetin, and α-mangostin [35,65,83,252,253].

3.5 Mitochondria ROS and the activation of pro-inflammatory mechanisms

In AKI, the initial injury leads to kidney inflammation as part of the reparatory mechanisms [254]. However, the persistence of the damage leads to CKD development [255,256]. Renal inflammation results from the activation of several pathways that are enhanced by ROS activation of the mitogen-activated protein kinase (MAPK) cascade, phosphoinositide-3-kinase (PI3K), renin-angiotensin- aldosterone system (RAAS) and NF-κB, pathway, increasing pro-inflammatory genes transcription [256,257] and DAMPs production [[258], [259], [260]]. Meanwhile, cell DAMPs are released and recognized by the toll-like (TLRs) and NLR receptors of target cells [237,258], including mitochondrial DAMPs, and can be packaged and transported by EVs to target cells [98,261,262]. ROS also induces the NRLP3-mediated release of pro-inflammatory EVs in podocytes [263].

Experimental AKI may induce increased left ventricular end-diastolic pressure (LVEDP) and cardiac fibrosis [264]. This phenomenon is intricately linked to the inflammatory cascade triggered by the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IFN-γ, which are associated with mitochondrial depolarization, ETS reduction, increased ROS production, and mitochondrial fission fragmentation [12,34,46,108,265,266]. The increase in TNF-α also triggers cardiac fibrosis by stimulating the extracellular matrix protein production (i.e., collagen), leading to myocardial stiffening and impaired function. It also promotes cardiac hypertrophy through the activation of NF-κB and MAPKs, contributing to cardiac remodeling and dysfunction [267]. Meanwhile, IL-6 stimulates cardiac hypertrophy by activating the JAK/STAT pathway. It also encourages fibrosis by upregulating TGF-β and CTGF. In this context, after 24 h of renal I/R, an impairment of OCR and ECAR is observed in myocardial tissue, along with cytochrome B release and cleaved caspase-3 [264,268]. Later, at 48h, Gal-3 expression increases in cardiac cells, accompanied by MCP-1 and CD68+ infiltrating macrophages [265], which reduces CIII and CIV activity and NRF1 nuclear translocation [269]. After 72h, cardiomyocytes swelling appears, and plasma BNP and Troponin T are significantly elevated. Meanwhile, cardiac Akt/mTOR signaling and mitochondrial bioenergetics are impaired, leading to reduced ATP production, inducing apoptosis, and ferroptosis [270,271]. In contrast, the anti-inflammatory molecule Klotho prevents an elevation of IL- 6, IL-1β, and TNF-α, and improves the calcium dysfunction of cardiomyocytes, which is associated with attenuated cardiac hypertrophy in AKI mice [272].

In addition, oxidative stress participates in the myocardial damage associated with types 3 and 4 CRS. The mtROS release triggers the NLRP3 inflammasome/IL-1β/IL-18 activation, by promoting the dissociation of thioredoxin-interacting protein (TXNIP) from thioredoxin (TRX) in both kidney and heart [46,273]. Activation of NOX4 also mediates pyroptosis, increases mitochondrial antiviral signaling protein (MAVS) [274,275], and diminishes the SIRT3 activity, SOD2 levels, and the GSH/GSSG ratio [276]. Consequently, this renal pro-oxidative state triggers the production of mitochondrial DAMPs and promotes the release of mitochondrial EVs (MitoEVs). The MitoEVs can carry mtDNA, rRNA, tRNA, mitochondrial proteins, including respiratory chain protein complexes, and intact mitochondria [277]. Interestingly, the increase in mtDNA in a CKD environment has been associated with cardiac hypertrophy, likely due to the activation of the cGAS-STING/TBK1/NF-κB pathway [278]. Similarly, patients under hemodialysis show a higher number of mtDNA copies in plasma, activation of TLR9-dependent pro-inflammatory signaling, and cardiovascular injury [279]. Increased MitoEVs are also found in chronic HF and cardiac ischemia [280].

4 Mitochondrial biogenesis impairment in CKD, AKI, and reno-cardiac disease

The AMPK-SIRT1/3-PGC-1α axis emerges as a central hub in mitochondrial biogenesis regulation. Metabolic reprogramming correlates with AMPK-SIRT1/3-PGC-1α-mediated mitochondrial biogenesis downregulation and increases inflammation [35,63,65,[78], [79], [80],281]. The AMPK/PGC-1α pathway is strongly regulated by SIRT 1 and 3 (Fig. 5), and PGC-1α stimulates the gene expression of SIRT3 [282,283]. SIRTs are NAD+-dependent histone deacetylases consisting of 7 members. Specifically, SIRT3 resides in the mitochondria, and SIRT1 is found in both the nucleus and the cytosol [257]. SIRTs are also important regulators of redox signaling [32]. In this regard, overregulation of SIRT1 and SIRT3 restores OXPHOS (Fig. 5), which reduces mitochondrial ROS production during renal damage and CRS. Upregulation of SIRT3-induced PGC-1α increases the expression of ROS-detoxifying enzymes and ETS subunits [230,282,283].Fig. 5 NAC Induction of the AMPK-SIRT1/3-PGC-1α Pathway. N-acetylcysteine (NAC) activates multiple targets within the AMPK-SIRT1/3-PGC-1α pathway, promoting cryoprotection. Activation of this pathway induces mitochondrial biogenesis and enhances the activity of OXPHOS enzymes, preserving mitochondrial mass. It also induces the overexpression of antioxidant enzymes, maintaining mitochondrial redox balance. Additionally, this pathway inhibits the activation of NF-κB, NLRP3, and TGF-β pathways induced by inflammatory mediators. This prevents PGC-1α inhibition and subsequent fibrotic processes. The dotted green lines symbolize the sites of action of the NAC. Ac: acetylation; AMPK: AMP-activated protein kinase; ARE: antioxidant response elements; DAMPs: damage-associated molecular patterns; GPx4: glutathione peroxidase; GR: glutathione reductase; NAC: N-acetylcysteine; NF-κB: nuclear factor kappa B; NRFs: nuclear respiratory factors; Nrf2: nuclear factor erythroid 2–related factor 2; NRLP3: NACHT, LRR, and PYD domains-containing protein 3; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen spices; mtROS: mitochondrial; PGC-1α: peroxisome proliferator-activated receptor-gamma coactivator; PPARs: peroxisome proliferator-activated receptors; SIRT1: sirtuin1; SIRT3: sirtuin3; SOD2: superoxide dismutase 2; TGF-β: transforming growth factor-beta. Figure created using BioRender.com (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).

Fig. 5

The AMPK-SIRT1/3-PGC-1α axis regulates the gene expression of mitochondrial transport, fatty acid oxidation, OXPHOS, and biogenesis proteins [284]. Since PGC-1α expression is suppressed during the AKI, CKD, and CRS transition by TGF-β and Smad-mediated pathways [34,211,[285], [286], [287]], this effect leads to significant oxidative stress. Likewise, SIRT3 overexpression in AKI promotes autophagy, preventing tubular cell apoptosis and the accumulation of pro-inflammatory cytokines in the kidney [288]. Interestingly, AMPK-SIRT1activation inhibits NF-KB and the expression of the NLRP3 inflammasome components, caspase-1, IL-1β, and gasdermin D in mice with diabetic nephropathy [289]. Another pathway related to SIRT1 during CKD is the C-Jun N-terminal kinase (JNK) pathway. JNK promotes inflammation, cell death, and fibrosis in CKD [290,291]. Conversely, preventing the joint signaling of JNK and Smad3 avoids the downregulation of PGC-1α in myofibroblasts and proximal tubular cells, thus preventing mitochondrial dysfunction in CKD and CRS [292]. Indeed, restoring mitochondrial biogenesis by means of antioxidants or PGC-1α agonists prevented inflammatory processes and fibrosis in AKI, CKD and CRS [34,35,55,61,293].

In this line, a reduction in the expression of mitochondrial biogenesis factors is observed in the kidney and in the heart (i.e., SIRT1, SIRT3, PGC1a, NRF-1, NRF-2, CPT1A, ATP5A) for both type-3 and -4 CRS [34,35,72]. In particular, the AMPK/SIRT1/3/PGC-1α axis emerges as a central component in coordinating mitochondrial biogenesis at the cardiac level [[294], [295], [296]], regulating the expression of genes encoding mitochondrial proteins [297,298] and also upregulating antioxidant enzymes, enhancing cardiomyocyte viability [299]. Of interest, the subcellular localization of AMPK, SIRT1/3, and PGC1a has been observed in both mitochondria and nuclei, suggesting a contribution of these organelles to maintaining mitochondrial homeostasis [300,301]. The most important changes reported in the proteins involved in this pathway are summarized in Table 1.Table 1 Mitochondrial homeostasis factors in CRS type 3 and 4. Variations of proteins [p-AMPK (phosphorylated AMP-activated protein kinase), PGC1a (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha, SIRT1/3 (Sirtuins 1 and 3), NRF1/2 (Nuclear Respiratory Factor 1 and 2), TFAM (mitochondrial transcription factor A), Drp1 (Dynamin-Related Protein 1), Fis1(Fission 1), Mitofusin 1 and 2 (Mfn 1/2), OPA1 (Optic Atrophy type 1), PINK1 (PTEN-induced putative kinase 1), BNIP3 (BCL2 interacting protein 3), FUNDC1 (FUN14 domain containing 1), and Microtubule-associated protein 1A/1B-light chain 3 (LC3)] of mitochondrial homeostasis are described in CRS type 3 and 4. Arrows indicate over- or down-regulation of factors. n.r., non-reported data.

Table 1	Factors	CRS Type 3	CRS Type 4	References	
Kidney	Heart	Kidney	Heart	
Mitochondrial Biogenesis	p-AMPK	↓	n.r.	↓↑↔	↓	[[302], [303], [304], [305]]	
PGC1a	↓	↓	↓	↓↔	[30,34,35,47,72,281]	
SIRT1	↓	↓	↓	↓	[34,306,307]	
SIRT3	↓↔	↓	↓	n.r.	[34,304,306,308]	
NRF1	↓	↓	↓	↓	[34,35,47,72,281,309]	
NRF2	↓	↓	↓	↓	[35,281,310]	
TFAM	↓	↓	↓	↓	[35,47,72,281,311]	
Mitochondrial Dynamic	Drp1	↑	↑↓	↑	↑↓	[30,34,281,308,311,312]	
Fis1	↑	↔↑	↔	↔	[30,35,281,313]	
Mfn1	↓	↔↑	↓	↓	[30,35,281,311]	
Mfn2	↔	↔↓↑	↓	↓	[12,34,35,281,311,312]	
OPA1	↓	↔↓	↓	↓	[34,35,281,312,313]	
Mitophagy	PINK1	↑↓	↑	↑↓↔	n.r.	[34,35,83,281,314,315]	
Parkin	↑↓	↓↔	↓↔	n.r.	[34,281,[314], [315], [316], [317]]	
BNIP3	↑	↑	↑	n.r.	[34,303,318,319]	
FUNDC1	↑	↓	↑	↓	[303,313,317,320,321]	
LC3	↓↑	↓	↓↑	↓↑	[35,83,281,309,310,313,316,321]	

On the other hand, recent studies have uncovered NAC-protective effects related to mitochondrial mass preservation through Sirtuins-AMPK-PGC1-α pathway activation [35,61,230,234,236]. In experimental diabetic nephropathy, NAC was found to inhibit ferroptosis by an SIRT3-SOD2/Gpx4 dependent pathway [322]. NAC also mitigates the detrimental effects of Bisphenol A in renal ischemia-reperfusion (IRI) injury by improving SIRT3-dependent mitochondrial biogenesis [323].

Mechanistically, NAC increased AMPK levels, thereby promoting SIRT3 transcription and enhancing the antioxidant response mediated by PGC-1α and Nrf2 (Fig. 5). SIRT1 and SIRT3 activation by NAC may inhibit inflammation by oxidative stress reduction and mitochondrial biogenesis induction in CKD and CRS type 3 [34,64,79,281]. Likewise, NAC enhances SOD2 antioxidant activity in mitochondria through SIRT3-mediated deacetylation [282,323]. NAC also restores the levels of antioxidant enzymes SOD2 and GPx and the ETS complexes and Krebs cycle enzyme activities [34,324]. Importantly, stimulation of the renal AMPK/SIRT1/3/PGC-1α axis decreases mtROS production and NLRP3 inflammasome/IL-1β/IL-18 activation during AKI, CKD and CRS [34,286,288,325,326]. Thus, NAC-induced mitochondrial protection may be a potential treatment to prevent inflammation in AKI, CKD and CRS [34,64,79,281] Besides, recent studies suggest that the activation of SIRT3 occurs by direct interaction with NAC [322], creating a new range of molecular targets. As is shown in Fig. 5, NAC effects on SIRTs regulation can be diverse given its multifaceted capabilities. These findings underscore NAC's therapeutic potential in mitigating mitochondrial biogenesis and inflammation by AMPK-SIRT1/3-PGC-1α activation.

4.1 In silico interaction between NAC and SIRT1/3

The potential interaction and activation of SIRT1/3 by NAC could be tested using in silico tools like molecular docking; in this way, it is possible to have a better view of the molecular interaction between these molecular targets and the NAC, and reinforce the experimental evidence that suggests the activation of SIRT1/3 by NAC [230,234,236,286,327].

It is remarkable all the studies around the search of activating compounds for these two enzymes [323,328,329], especially for the important role than they play in CKD [282,283,288]. The activation of SIRT1/3 implies an improve of their catalytic activity without interfering with NAD+ interaction, taking in account this important union and for a better understand of this section we summarize the principal structural features of all the SIRTs isoforms: 1) a Rossman domain that contains the catalytic and the NAD+ binding amino acids, 2) a region with the amino acids that allow the union with the atom of zinc, and 3) an N and C-terminal domains with different regulatory and recognizing activity [330,331]; although SIRT1/3 have remarkable structural similarities, they show different 3D structure [332]. Therefore, the link of activation molecules when the NAD+ is linked will occur in different structural sites. In the case of SIRT1, the predominant interactions happen in the N-terminal domain [329,331,333], one example it is the complex SIRT1-resveratrol [333]. On the other hand, for SIRT3 the activating compounds like honokiol, binds near the NAD+ interacting zone. Notably, the formation of these complex has been reported to reduce damage in heart and renal diseases, making it an important therapeutic strategy [323,328,330,334,335].

To predict the main possible regions of interaction between NAC and SIRT1 and SIRT3. we used resveratrol and honokiol as positive controls [333,334] for SIRT1 (PDB ID:4ZZJ) and SIRT3 (PDB ID: 5H4D), used the PDB crystallography structure. The docking simulation was carried out using AutoDock4Zn and AutoDockTools [336], with a grid of 60 × 60 × 60 Å. The coordinates were selected based on the previous interaction with the positive controls. Chimera [337] was employed for the preparation of protein structures and figures. Finally, Spartan (Wavefunction Inc., Irvine, CA, USA) was used to optimize positive control compounds, considering the protonation form for each case.

As result, NAC has a similar union region like the resveratrol (SIRT1) and honokiol (SIRT3). The changes in the bond energies (ΔG) and the amino acids of interaction could be explained by the intrinsic molecular structure of NAC. The SIRT1-NAC complex presented a ΔG = −3.1 kcal/mol, showing the most favorable interaction in the alpha 1 (α1) and 2 (α2) helices at the N-terminal domain; the main forces observed in the complex SIRT1-NAC were van der Waals (Leu192, Ile225, Val188, Trp221, Met218, Gln222), hydrogen bonds (Gln189 and Thr185), and a very stable π-anion (Try185 and O− of the deprotonated carboxyl group) (Fig. 6A). NAC showed some of the same amino acids of interaction showed by resveratrol (ΔG = −5.1 kcal/mol) with the main difference that resveratrol interacts more with the amino acids in the α3.Fig. 6 NAC Interaction with SIRT1 and SIRT3. (A) SIRT1: Ribbon representation of SIRT1 (PDB ID: 4ZZJ) and its complexes with NAC (yellow sticks), resveratrol (magenta sticks), and a NAD+ derivative (Carba-nicotinamide-adenine-dinucleotide; orange sticks). Magenta lines indicate hydrogen bonds between NAC and SIRT1. The green sphere represents a zinc atom. (B) SIRT3: Ribbon representation of SIRT3 (PDB ID: 5H4D) and its complexes with NAC (yellow sticks), honokiol (cyan sticks), and NAD+ (orange sticks). The green sphere represents a zinc atom. Magenta lines indicate hydrogen bonds. NAC may activate SIRT1 and SIRT3 through direct interaction with their structural regions. Figure created using BioRender.com (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article).

Fig. 6

In the case of SIRT3, the important area where NAC interacted was near the hydrophilic cavity occupied by NAD+ and honokiol with a ΔG = −4.6 kcal/mol. Also, it was observed that this area was mainly composed of loops. The predominant interactions were hydrogen bonds Gln228, His248, Thr320, Ser321, Leu322, Glu323, and Val324) and van der Waals forces (Glu325 and Pro326) (Fig. 6B). All these interactions could be explained by the complete deprotonation of NAC in the mitochondrial matrix. Finally, we observed that honokiol (ΔG = −6.8 kcal/mol) had a larger surface area, improving its interaction with a greater number of amino acids in the loops of this cavity. Still, the number of hydrogen bonds was lower than that of NAC, increasing the formation of a more stable complex with this compound.

Based on the obtained results, the activation of SIRT1 and SIRT3 could be initiated by NAC's direct interaction with each enzyme's structural regions. The last assumption was supported by the fact that NAC exhibited binding sites comparable to those presented by the most studied activators of each one of these enzymes. Therefore, this opens the door to uncovering new regulatory mechanisms in the mitochondrial physiology of NAC that were previously unknown.

4.2 Mitochondrial dynamics and mitophagy in CRS

Mitochondrial fusion and fission can also be compromised in type-3 and -4 CRS [294]. In AKI and CKD, dysfunctional mitochondria may release mtDNA to activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, promoting an inflammatory environment with overexpression of p-p65, p-IRF3 and TBK1, and tubular damage [308,338]. In AKI mice, alterations in cardiac mitochondrial dynamics were also evidenced by the increased expression of dynamin-related protein 1 (Drp1) and Fis1, while Mfn2 and OPA1 were decreased, leading to enhanced mitochondrial fragmentation. This phenomenon may explain the subsequent inflammatory response (i.e., increases in IL-6, MCP-1, TNFα), cellular apoptosis, and cardiac dysfunction. Notably, inhibition of Drp1 attenuated these events [12,313]. In CKD mice, cardiomyocytes showed a cytosolic increase in mtDNA, which stimulates the cGAS-STING–NF– κB pathway to favor cardiac hypertrophy [278]. They also exhibited mitochondrial fragmentation, elevated levels of Drp1, but reduced Mfn1/2, and mitophagy [30,309]. Deficiencies in PTEN-induced kinase 1 (PINK1) and Parkinson disease protein 2 (PARK2) have been correlated with mitochondrial fragmentation, ROS production, and inflammation in renal tubular cells of AKI and CKD models [339,340]. Also, PINK1/Parkin activity is crucial to protect against cardiac damage through its role in preventing mitochondrial dysfunction and the increase in ROS, which may result in oxidative damage in cardiomyocytes [341]. In I/R-induced AKI and CKD, a reduction in cardiac FUN14 domain-containing protein 1 (FUNDC1) and other key mitophagy markers such as mitochondrial-associated microtubule light chain 3II (mito-LC3II), Beclin1, and autophagy-related gene 5 (Atg5) were associated with mitochondria fragmentation [313,321].

Altogether, as shown in Fig. 7, alterations in mitochondrial homeostasis in type-3 and -4 CRS highlight the crucial role of mitochondrial dynamics in these disorders. Moreover, the underlying mechanisms in these reno-cardiac pathologies involve sympathetic hyperactivation of the SNS and RAAS, inflammation, and the production of uremic toxins. All of these could be directly or indirectly interconnected to mitochondrial dysfunction [46,342].Fig. 7 Molecular Crosstalk Between Injured Kidney and Heart. The precise mechanisms of communication between acute or chronic kidney injury (AKI/CKD) and the heart remain incompletely understood. However, following AKI or CKD, the kidney releases various factors into circulation: Pro-inflammatory factors: TNF-α, Galectin-3 (Gal-3), IL-1β, IL-6, IFN-γ; Vasoactive factors: Angiotensin II (Ang II); Damage-associated molecular patterns (DAMPs): Mitochondrial DNA (mtDNA); Uremic toxins (UTs): Indoxyl sulfate (IS), Indole-3-acetic acid (IAA). These factors can promote monocyte differentiation into macrophages. Additionally, some can be encapsulated and released within extracellular vesicles (EVs). Upon reaching the myocardium, these factors, both free and encapsulated in EVs, can activate the NF-κB pathway via Toll-like receptors (TLRs), interleukin receptors (ILRs), tumor necrosis factor receptor (TNFR), and Ang II receptor type 1 (AT1). This leads to the upregulation of pro-inflammatory factors (IL-1β, IL-18, TNF-α, IL-6) and the NLRP3 inflammasome, contributing to oxidative stress and mitochondrial injury. Free and encapsulated mtDNA may further exacerbate these effects through the cGAS-STING-IRF3 and TLR9-NF-κB pathways. Uremic toxins can also bind to the aryl hydrocarbon receptor (AhR), promoting NF-κB activation and contributing to the pro-inflammatory environment. The resulting mitochondrial dysfunction is characterized by decreased electron transport system activity (complexes I–V), reduced ATP production, and impaired antioxidant defenses (SOD2, CAT, GPx), ultimately leading to mitochondrial disruption and cell death via apoptosis and pyroptosis. Figure created usingBioRender.com.

Fig. 7

4.3 Activation of the neurohormonal systems

During AKI, hypoperfusion and hypovolemia reduce the mean arterial pressure (MAP) through the activation of the sympathetic nervous system (SNS) [343]. In fact, an elevation of norepinephrine (NE) was observed in critically ill AKI patients [344]. Similarly, sympathetic hyperactivity is present from the early stages of CKD, leading to a worse renal prognosis [345,346]. Also, in rodents, AKI and CKD trigger hyperactivation of the renal sympathetic nervous system, increasing NE levels [[347], [348], [349]], which impairs calcium homeostasis and mitochondrial respiration in the heart by opening mitochondrial permeability transition pores (mPTP), thus producing ROS, and releasing cytochrome C [350]. The SNS stimulation also activates β1-adrenergic receptors at the juxtaglomerular apparatus, resulting in renin upregulation and release [351,352]. The decreased renal plasma flow and NaCl delivery to the macula densa also enhance Ang II levels and expression of its AT1 receptor [30,266].

Interestingly, excessive or prolonged activation of SNS and RAAS also lead to deleterious effects on cardiovascular health [353]. In AKI and CKD models, cardiac disruption of calcium and upregulation of NE, β1-adrenergic receptors, and FGF-23 have been described [266,354,355]. These responses mediate HF and arrhythmia. Also, AngII via the AT1 receptor activates NOX2 and NOX4, to elevate ROS and reduce the antioxidant defense, contributing to oxidative stress and heart mitochondrial damage [356,357]. However, the administration of melatonin, an enhancer of mitochondrial biogenesis by activating the AMPK/SIRT1/PGC1a axis, reverses these abnormalities [30,358,359]. As expected, atenolol, losartan, and enalapril improve cardiac structure and function after AKI by blocking SNS or RAAS hyperactivation [266].

4.4 Release of uremic toxins

The European Uremic Toxins Working Group (EUTox) has cataloged 146 substances that may accumulate in the body due to a reduced renal clearance, termed uremic retention solutes (URS). Currently, 130 URS are detailed in the EUTox database and some of them are classified as uremic toxins (UTs) [360,361]. The toxicity of these molecules affects numerous cellular processes, including mitochondrial respiration. Roughly, 25 % of the UTs may affect mitochondrial function, and mitochondria also serve as a provider of these molecules [362]. In particular, gut-derived UTs (i.e., indoxyl sulfate (IS), p-cresyl sulfate (pCS), indole-3-acetic acid (IAA)) are associated with mitochondrial dysfunction and cardiovascular complications arising from both AKI and CKD [[362], [363], [364]] Administration of IS and IAA to isolated mitochondria altered OXPHOS and the activity of complex III and IV [107]. Also, IS and pCS reduced PGC1a, Mfn2, and Mfn1 while upregulating Drp1, resulting in ROS deposition [365,366]. IS also promotes endoplasmic reticulum stress (ERS) and the subsequent apoptosis of cardiomyocytes [367]. An elevation of IS after I/R-induced AKI is correlated with acute cardiac dysfunction in a pro-oxidant, proinflammatory, and proapoptotic context. This scenario is partially reversed by AST-120, an oral charcoal adsorbent with the capacity to neutralize indole [368]. Furthermore, systemic therapy with endothelial progenitor cells (EPC) that prevent renal injury and lower plasma IS levels mitigated cardiac dysfunction [369].

Similarly, an independent association has been observed between IS and left ventricular hypertrophy in patients and models of CKD [370]. IS increases ROS and decreases SIRT1 activity through the aryl hydrocarbon receptor (AhR)/NADPH oxidase pathway [371,372]. IS also activates NLRP3 via the AhR/NF-κB pathway in the cardiac failure associated with CKD [373]. Activation of AhR is related to the upregulation of proinflammatory molecules and the downregulation of fatty acid oxidation and mitochondrial biogenesis [374]. Moreover, IAA stimulated the AhR/NF-κB pathway, leading to cardiac oxidative stress and inflammation in patients with CKD [375]. Interestingly, stimulation of cardiac cells with uremic serum from CKD patients induces mitochondrial fragmentation and dysfunction in the heart [376]. Lastly, the accumulation of pCS after CKD augments the NADPH oxidase activity and ROS, contributing to cardiac apoptosis and diastolic dysfunction [377].

5 Final remarks

The heart and kidney, the organs with the highest mitochondrial density, share a close intercommunication vital for maintaining mitochondrial homeostasis and ensuring proper function. Mitochondrial bioenergetics and redox imbalances are intrinsically linked to the progression from AKI to CKD. Recent evidence reveals that similar alterations in cardiac tissues are key in the pathways involved in CRS type 3 and 4 developments.

Pathological bioenergetic alteration in both organs are characterized by metabolic reprograming from oxidative to anaerobic metabolism. This leads to the decrease in Krebs cycle, β-oxidation and ETS activity and metabolism, as well as its intermediary metabolites. In the kidney, the high dependence of the mitochondrial β-oxidation and the inability to use the glycolytic pathway in PCT decreases gluconeogenesis and severely impacts the glucose supply to medullary segments. This favors a global decrease in ATP levels and ΔΨm depolarization, processes that enhance oxidative stress and the release of cardio-renal mediators by renal tissue. Although the heart's greater glycolytic capacity allows for the early ATP level compensation, experimental evidence in the CRS type 3 and 4 demonstrates that this metabolic reprograming from β-oxidation to glycolysis finally induces an energy crisis, promoting cell death, inflammation and cardiac remodeling leading to dysfunction.

Mitochondrial impairment is also linked with the redox imbalances as a result in the increase in ROS production by this organelle. In both organs this pro-oxidant state is strongly linked to the reduction in the activity of the Krebs cycle and ETS. While in the physiological context, the high capacity of GSH-dependent antioxidant systems and the high de novo GSH synthesis capacity in the kidney, allow for facing redox imbalance, in AKI and CKD GSH/GSSG ratios rapidly decrease in cytosolic and mitochondrial compartments. This induces a reduction in the RS-SG protective mechanism, further impairing bioenergetic pathways, especially ETS. Moreover, GSH depletion promotes several ROS-induced inflammatory pathways, enhancing renal secretion of pro-inflammatory cytokines and EVs. This redox imbalance is also observed from early stages in CRS, associated with the lower capacity of GSH-dependent antioxidant system in the heart. Furthermore, recent evidence suggests that RS-SG loss also impairs OXPHOS in cardiomyocytes.

Finally, mitochondrial redox and bioenergetics impairments are closely related to the downregulation of the AMPK-SIRT1/3-PGC-1α axis, reducing mitochondrial biogenesis in the transition from AKI to CKD and CRS. As shown, increased ROS levels downregulate mitochondrial biogenesis proteins reducing mitochondria mass and antioxidant gene expression and enhancing pro-inflammatory pathways and cell death in cardiac and renal tissues. In this regard, the use of antioxidants that induce GSH synthesis RS-SG levels has emerged as an integral strategy to preserve mitochondrial bioenergetics and redox homeostasis by activating several targets in AMPK-SIRT1/3-PGC-1α axis. This strategy has shown promise in reducing renal damage in the AKI to CKD transition, as well as the release of pro-inflammatory cytokines and the increase in cardio-renal connectors, like EVs release from the kidney. Antioxidants like NAC have been shown to activate AMPK and SIRTs, enhancing mitochondrial biogenesis, which inhibits metabolic reprogramming, inflammation and oxidative in CRS type 3 and IV. Although this pathway has been recently studied in AKI an CKD, and NAC effects on AMPK-SIRT1/3-PGC-1α axis have been shown to be diverse given its multifaceted capabilities, the elucidation of the mechanism states could be very useful to expose molecular targets that prevent mitochondrial alterations that favor the CSR. However, deeper studies basic and clinic levels are still necessary in this field for the development of novel treatment strategies.

In conclusion, the intricate interplay between mitochondrial dysfunction, bioenergetic alterations, and redox imbalances in both the heart and kidney plays a pivotal role in the progression from AKI to CKD and the development of CRS. The shift from oxidative to anaerobic metabolism, coupled with compromised redox balance and disrupted mitochondrial biogenesis, fuels a vicious cycle of inflammation, and cellular damage in both organs. While antioxidants like NAC have shown promise in mitigating these effects by targeting the AMPK-SIRT1/3-PGC-1α axis, further research is needed to fully elucidate the underlying mechanisms and explore novel therapeutic strategies to prevent mitochondrial dysfunction and its detrimental consequences in reno-cardiac pathologies.

Funding

Open Access funding for this article was supported by the Instituto Nacional de Cardiología Ignacio Chávez. Partial funding for the results presented in this review was provided by Fondos de Gasto Directo Autorizados a la Subdirección de Investigación Básica del Instituto Nacional de Cardiología Ignacio Chávez (protocol number 21-125 ) and Consejo Nacional de Humanidades, Ciencia y Tecnología (CONAHCyT; Grants CBF2023-2024-190 and CF-2023-I-1083 ).

CRediT authorship contribution statement

Jairo Lumpuy-Castillo: Writing – review & editing, Writing – original draft, Visualization, Investigation. Isabel Amador-Martínez: Writing – review & editing, Writing – original draft, Methodology, Investigation, Conceptualization. Miriam Díaz-Rojas: Writing – original draft, Software, Methodology, Investigation, Formal analysis, Conceptualization. Oscar Lorenzo: Writing – review & editing, Supervision, Formal analysis, Conceptualization. José Pedraza-Chaverri: Writing – review & editing, Supervision, Resources, Funding acquisition. Laura Gabriela Sánchez-Lozada: Writing – review & editing, Writing – original draft, Supervision, Resources, Funding acquisition, Conceptualization. Omar Emiliano Aparicio-Trejo: Writing – review & editing, Writing – original draft, Visualization, Supervision, Resources, Project administration, Methodology, Funding acquisition, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.

Acknowledgments

Isabel Amador-Martínez is a student in the Programa de Doctorado en Ciencias Biológicas at 10.13039/501100005739 Universidad Nacional Autónoma de México (UNAM). She was a recipient of the fellowship 780369 from CONAHCyT.
==== Refs
References

1 Ronco C. McCullough P. Anker S.D. Anand I. Aspromonte N. Bagshaw S.M. Bellomo R. Berl T. Bobek I. Cruz D.N. Daliento L. Davenport A. Haapio M. Hillege H. House A.A. Katz N. Maisel A. Mankad S. Zanco P. Mebazaa A. Palazzuoli A. Ronco F. Shaw A. Sheinfeld G. Soni S. Vescovo G. Zamperetti N. Ponikowski P. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative Eur. Heart J. 31 2010 703 711 10.1093/eurheartj/ehp507 20037146
2 Georgopoulou T. Petrakis I. Dermitzaki K. Pleros C. Drosataki E. Aletras G. Foukarakis E. Lioudaki E. Androulakis E. Stylianou K. Cardiorenal syndrome: challenges in everyday clinical practice and key points towards a better management J. Clin. Med. 12 2023 4121 10.3390/jcm12124121 37373813
3 Pliquett R.U. Cardiorenal syndrome: an updated classification based on clinical hallmarks J. Clin. Med. 11 2022 10.3390/jcm11102896
4 Mavrakanas T.A. Khattak A. Singh K. Charytan D.M. Epidemiology and natural history of the cardiorenal syndromes in a cohort with echocardiography, Clin J. Am. Soc. Nephrol. 12 2017 1624 1633 10.2215/CJN.04020417
5 Kellum J.A. Romagnani P. Ashuntantang G. Ronco C. Zarbock A. Anders H.J. Acute kidney injury Nat. Rev. Dis. Prim. 7 2021 10.1038/s41572-021-00284-z
6 Odutayo A. Wong C.X. Farkouh M. Altman D.G. Hopewell S. Emdin C.A. Hunn B.H. AKI and long-term risk for cardiovascular events and mortality J. Am. Soc. Nephrol. 28 2017 377 387 10.1681/ASN.2016010105 27297949
7 De Clercq L. Ailliet T. Schaubroeck H. Hoste E.A.J. Acute and chronic cardiovascular consequences of acute kidney injury: a systematic review and meta-analysis Cardiorenal Med. 13 2023 26 33 10.1159/000527198 36404711
8 Drubel K. Marahrens B. Ritter O. Patschan D. Kidney-related outcome in cardiorenal syndrome type 3 Internet J. Nephrol. 2022 2022 10.1155/2022/4895434
9 Pavan M. Incidence of acute cardiorenal syndrome type 3 in India, Iran J. Kidney Dis. 8 2014 42 45
10 Melo F.D.A.F. Macedo E. Bezerra A.C.F. De Melo W.A.L. Mehta R.L. Burdmann E.D.A. Zanetta D.M.T. A systematic review and meta-analysis of acute kidney injury in the intensive care units of developed and developing countries PLoS One 15 2020 1 26 10.1371/journal.pone.0226325
11 Diamantidis C.J. Zepel L. Smith V.A. Brookhart M.A. Burks E. Bowling C.B. Maciejewski M.L. Wang V. Epidemiology of community-acquired acute kidney injury among US veterans Am. J. Kidney Dis. Off. J. Natl. Kidney Found. 82 2023 300 310 10.1053/j.ajkd.2023.01.448
12 Sumida M. Doi K. Ogasawara E. Yamashita T. Hamasaki Y. Kariya T. Takimoto E. Yahagi N. Nangaku M. Noiri E. Regulation of mitochondrial dynamics by Dynamin- related protein-1 in acute cardiorenal syndrome J. Am. Soc. Nephrol. 26 2015 2378 2387 10.1681/ASN.2014080750 25644112
13 Alarcon M.M.L. Trentin-Sonoda M. Panico K. Schleier Y. Duque T. Moreno-Loaiza O. de Yurre A.R. Ferreira F. Caio-Silva W. Coury P.R. Paiva C.N. Medei E. Carneiro-Ramos M.S. Cardiac arrhythmias after renal I/R depend on IL-1β J. Mol. Cell. Cardiol. 131 2019 101 111 10.1016/j.yjmcc.2019.04.025 31029578
14 Legrand M. Rossignol P. Cardiovascular consequences of acute kidney injury N. Engl. J. Med. 382 2020 2238 2247 10.1056/nejmra1916393 32492305
15 Wang H. Lambourg E. Guthrie B. Morales D.R. Donnan P.T. Bell S. Patient outcomes following AKI and AKD: a population-based cohort study BMC Med. 20 2022 1 17 10.1186/s12916-022-02428-8 35000596
16 Abdala P.M. Swanson E.A. Hutchens M.P. Meta-analysis of AKI to CKD transition in perioperative patients, Perioper Méd. 10 2021 1 7 10.1186/s13741-021-00192-6
17 Szlagor M. Dybiec J. Młynarska E. Rysz J. Franczyk B. Chronic kidney disease as a comorbidity in heart failure Int. J. Mol. Sci. 24 2023 1 14 10.3390/ijms24032988
18 GBD Chronic Kidney Disease Collaboration Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet (London, England) 395 2020 709 733 10.1016/S0140-6736(20)30045-3 32061315
19 Xue Y. Xu B. Su C. Han Q. Wang T. Tang W. Cardiorenal syndrome in incident peritoneal dialysis patients: what is its effect on patients' outcomes? PLoS One 14 2019 1 12 10.1371/journal.pone.0218082
20 Prothasis M. Varma A. Gaidhane S. Kumar S. Khatib N. Zahiruddin Q. Gaidhane A. Prevalence, types, risk factors, and outcomes of cardiorenal syndrome in a rural population of central India: a cross-sectional study J. Fam. Med. Prim. Care 9 2020 4127 10.4103/jfmpc.jfmpc_533_20
21 Suresh H. S A.B. Moger V. Swamy M. Cardiorenal syndrome type 4: a study of cardiovascular diseases in chronic kidney disease Indian Heart J. 69 2017 11 16 10.1016/j.ihj.2016.07.006 28228293
22 Levin A. Tonelli M. Bonventre J. Coresh J. Donner J.-A. Fogo A.B. Fox C.S. Gansevoort R.T. Heerspink H.J.L. Jardine M. Kasiske B. Köttgen A. Kretzler M. Levey A.S. Luyckx V.A. Mehta R. Moe O. Obrador G. Pannu N. Parikh C.R. Perkovic V. Pollock C. Stenvinkel P. Tuttle K.R. Wheeler D.C. Eckardt K.-U. ISN Global Kidney Health Summit participants, Global kidney health 2017 and beyond: a roadmap for closing gaps in care, research, and policy Lancet (London, England) 390 2017 1888 1917 10.1016/S0140-6736(17)30788-2 28434650
23 Jager K.J. Kovesdy C. Langham R. Rosenberg M. Jha V. Zoccali C. A single number for advocacy and communication—worldwide more than 850 million individuals have kidney diseases Kidney Int. 96 2019 1048 1050 10.1016/j.kint.2019.07.012 31582227
24 Bansal N. Katz R. Robinson-Cohen C. Odden M.C. Dalrymple L. Shlipak M.G. Sarnak M.J. Siscovick D.S. Zelnick L. Psaty B.M. Kestenbaum B. Correa A. Afkarian M. Young B. De Boer I.H. Absolute rates of heart failure, coronary heart disease, and stroke in chronic kidney disease: an analysis of 3 community-based cohort studies JAMA Cardiol 2 2017 314 318 10.1001/jamacardio.2016.4652 28002548
25 Minciunescu A. Genovese L. deFilippi C. Cardiovascular alterations and structural changes in the setting of chronic kidney disease: a review of cardiorenal syndrome type 4, SN compr Clin. Med. 5 2022 10.1007/s42399-022-01347-2
26 Segall L. Nistor I. Covic A. Heart failure in patients with chronic kidney disease: a systematic integrative review BioMed Res. Int. 2014 2014 10.1155/2014/937398
27 Yu A.S. Pak K.J. Zhou H. Shaw S.F. Shi J. Broder B.I. Sim J.J. All-cause and cardiovascular-related mortality in CKD patients with and without heart failure: a population-based cohort study in kaiser permanente southern California Kidney Med 5 2023 100624 10.1016/j.xkme.2023.100624
28 Bhargava P. Schnellmann R.G. Mitochondrial energetics in the kidney Nat. Rev. Nephrol. 13 2017 629 646 10.1038/nrneph.2017.107 28804120
29 Hamzaoui M. Djerada Z. Brunel V. Mulder P. Richard V. Bellien J. Guerrot D. 5/6 nephrectomy induces different renal, cardiac and vascular consequences in 129/Sv and C57BL/6JRj mice Sci. Rep. 10 2020 1 9 10.1038/s41598-020-58393-w 31913322
30 Bigelman E. Cohen L. Aharon-Hananel G. Levy R. Rozenbaum Z. Saada A. Keren G. Entin-Meer M. Pathological presentation of cardiac mitochondria in a rat model for chronic kidney disease PLoS One 13 2018 e0198196 10.1371/journal.pone.0198196
31 Mailloux R.J. Treberg J.R. Protein S-glutathionlyation links energy metabolism to redox signaling in mitochondria Redox Biol. 8 2016 110 118 10.1016/j.redox.2015.12.010 26773874
32 Singh C.K. Chhabra G. Ndiaye M.A. Garcia-Peterson L.M. MacK N.J. Ahmad N. The role of sirtuins in antioxidant and redox signaling Antioxidants Redox Signal. 28 2018 643 661 10.1089/ars.2017.7290
33 Ceballos-Picot I. Witko-Sarsat V. Merad-Boudia M. Nguyen A.T. Thévenin M. Jaudon M.C. Zingraff J. Verger C. Jungers P. Descamps-Latscha B. Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure Free Radic. Biol. Med. 21 1996 845 853 10.1016/0891-5849(96)00233-X 8902530
34 Cuevas-López B. Romero-Ramirez E.I. García-Arroyo F.E. Tapia E. León-Contreras J.C. Silva-Palacios A. Roldán F.-J. Campos O.N.M. Hernandez-Esquivel L. Marín-Hernández A. Gonzaga-Sánchez J.G. Hernández-Pando R. Pedraza-Chaverri J. Sánchez-Lozada L.G. Aparicio-Trejo O.E. NAC pre-administration prevents cardiac mitochondrial bioenergetics, dynamics, biogenesis, and redox alteration in folic acid-AKI-induced cardio-renal syndrome type 3 Antioxidants 12 2023 1592 10.3390/antiox12081592 37627587
35 Aparicio-Trejo O.E. Reyes-Fermín L.M. Briones-Herrera A. Tapia E. León-Contreras J.C. Hernández-Pando R. Sánchez-Lozada L.G. Pedraza-Chaverri J. Protective effects of N-acetyl-cysteine in mitochondria bioenergetics, oxidative stress, dynamics and S-glutathionylation alterations in acute kidney damage induced by folic acid Free Radic. Biol. Med. 130 2019 379 396 10.1016/j.freeradbiomed.2018.11.005 30439416
36 Tian Z. Liang M. Renal metabolism and hypertension Nat. Commun. 12 2021 1 12 10.1038/s41467-021-21301-5 33397941
37 Redfors B. Bragadottir G. Sellgren J. Swärd K. Ricksten S.E. Acute renal failure is NOT an “acute renal success”-a clinical study on the renal oxygen supply/demand relationship in acute kidney injury Crit. Care Med. 38 2010 1695 1701 10.1097/CCM.0b013e3181e61911 20512036
38 O'Connor P.M. Renal oxygen delivery: matching delivery to metabolic demand Clin. Exp. Pharmacol. Physiol. 33 2006 961 967 10.1111/j.1440-1681.2006.04475.x 17002675
39 McDonough A.A. Thomson S.C. Metabolic basis of solute transport Brenner and Rector's the Kidney 2012 138 157 10.1016/b978-1-4160-6193-9.10004-1
40 Klein K.L. Wang M.S. Torikai S. Davidson W.D. Kurokawa K. Substrate oxidation by isolated single nephron segments of the rat Kidney Int. 20 1981 29 35 10.1038/ki.1981.100 7300110
41 Hall A.M. Rhodes G.J. Sandoval R.M. Corridon P.R. Molitoris B.A. In vivo multiphoton imaging of mitochondrial structure and function during acute kidney injury Kidney Int. 83 2014 72 83 10.1038/ki.2012.328
42 Hall A.M. Unwin R.J. Parker N. Duchen M.R. Multiphoton imaging reveals differences in mitochondrial function between nephron segments J. Am. Soc. Nephrol. 20 2009 1293 1302 10.1681/ASN.2008070759 19470684
43 Legouis D. Faivre A. Cippà P.E. De Seigneux S. Renal gluconeogenesis: an underestimated role of the kidney in systemic glucose metabolism Nephrol. Dial. Transplant. 37 2022 1417 1425 10.1093/ndt/gfaa302 33247734
44 Adams R.A. Liu Z. Hsieh C. Marko M. Lederer W.J. Jafri M.S. Mannella C. Structural analysis of mitochondria in cardiomyocytes: insights into bioenergetics and membrane remodeling Curr. Issues Mol. Biol. 45 2023 6097 6115 10.3390/cimb45070385 37504301
45 Lopaschuk G.D. Karwi Q.G. Tian R. Wende A.R. Abel E.D. Cardiac energy metabolism in heart failure Circ. Res. 128 2021 1487 1513 10.1161/CIRCRESAHA.121.318241 33983836
46 Amador-Martínez I. Aparicio-Trejo O.E. Bernabe-Yepes B. Aranda-Rivera A.K. Cruz-Gregorio A. Sánchez-Lozada L.G. Pedraza-Chaverri J. Tapia E. Mitochondrial impairment: a link for inflammatory responses activation in the cardiorenal syndrome type 4 Int. J. Mol. Sci. 24 2023 15875 10.3390/ijms242115875
47 Dong X. Wen R. Xiong Y. Jia X. Zhang X. Li X. Zhang L. Li Z. Zhang S. Yu Y. Li Q. Wu X. Tu H. Chen Z. Xian S. Wang L. Wang C. Jia L. Wang J. Chen G. Emodin alleviates CRS4‐induced mitochondrial damage via activation of the PGC1α signaling Phyther. Res. 38 2024 1345 1357 10.1002/ptr.8091
48 Nishi H. Higashihara T. Inagi R. Lipotoxicity in kidney, heart, and skeletal muscle dysfunction Nutrients 11 2019 1 17 10.3390/nu11071664
49 Szeto H.H. Liu S. Soong Y. Alam N. Prusky G.T. Seshan S.V. Protection of mitochondria prevents high-fat diet–induced glomerulopathy and proximal tubular injury Kidney Int. 90 2016 997 1011 10.1016/j.kint.2016.06.013 27519664
50 Ceja-Galicia Z.A. García-Arroyo F.E. Aparicio-Trejo O.E. El-Hafidi M. Gonzaga-Sánchez G. León-Contreras J.C. Hernández-Pando R. Guevara-Cruz M. Tovar A.R. Rojas-Morales P. Aranda-Rivera A.K. Sánchez-Lozada L.G. Tapia E. Pedraza-Chaverri J. Therapeutic effect of curcumin on 5/6nx hypertriglyceridemia: association with the improvement of renal mitochondrial β-oxidation and lipid metabolism in kidney and liver Antioxidants 11 2022 2195 10.3390/antiox11112195 36358567
51 Moosavi S.M.S. Ashtiyani S.C. Hosseinkhani S. Shirazi M. Comparison of the effects of l-carnitine and α-tocopherol on acute ureteral obstruction-induced renal oxidative imbalance and altered energy metabolism in rats Urol. Res. 38 2010 187 194 10.1007/s00240-009-0238-9 19940986
52 Sun L. Halaihel N. Zhang W. Rogers H. Levi M. Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus J. Biol. Chem. 277 2002 18919 18927 10.1074/jbc.M110650200 11875060
53 Ceja-Galicia Z.A. Aranda-Rivera A.K. Amador-Martínez I. Aparicio-Trejo O.E. Tapia E. Trujillo J. Ramírez V. Pedraza-Chaverri J. The development of dyslipidemia in chronic kidney disease and associated cardiovascular damage, and the protective effects of curcuminoids Foods 12 2023 921 10.3390/foods12050921 36900438
54 Barter P. Lipoprotein metabolism and CKD: overview Clin. Exp. Nephrol. 18 2014 243 246 10.1007/s10157-013-0866-9 24052157
55 Kang H.M. Ahn S.H. Choi P. Ko Y.A. Han S.H. Chinga F. Park A.S.D. Tao J. Sharma K. Pullman J. Bottinger E.P. Goldberg I.J. Susztak K. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development Nat. Med. 21 2015 37 46 10.1038/nm.3762 25419705
56 Schaub J.A. Venkatachalam M.A. Weinberg J.M. Proximal tubular oxidative metabolism in acute kidney injury and the transition to CKD Kidney 2 2021 355 364 10.34067/KID.0004772020
57 Souza A.C.P. Bocharov A.V. Baranova I.N. Vishnyakova T.G. Huang Y.G. Wilkins K.J. Hu X. Street J.M. Alvarez-Prats A. Mullick A.E. Patterson A.P. Remaley A.T. Eggerman T.L. Yuen P.S.T. Star R.A. Antagonism of scavenger receptor CD36 by 5A peptide prevents chronic kidney disease progression in mice independent of blood pressure regulation Kidney Int. 89 2016 809 822 10.1016/j.kint.2015.12.043 26994575
58 Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL Cell 93 1998 241 252 10.1016/S0092-8674(00)81575-5 9568716
59 Jun H. Song Z. Chen W. Zanhua R. Yonghong S. Shuxia L. Huijun D. In vivo and in vitro effects of SREBP-1 on diabetic renal tubular lipid accumulation and RNAi-mediated gene silencing study, Histochem Cell Biol. 131 2009 327 345 10.1007/s00418-008-0528-2
60 Li Y. Liu Y. Huang Y. Yang K. Xiao T. Xiong J. Wang K. Liu C. He T. Yu Y. Han W. Wang Y. Bi X. Zhang J. Huang Y. Zhang B. Zhao J. IRF-1 promotes renal fibrosis by downregulation of Klotho Faseb. J. 34 2020 4415 4429 10.1096/fj.201902446R 31965641
61 Aparicio-Trejo O.E. Avila-Rojas S.H. Tapia E. Rojas-Morales P. León-Contreras J.C. Martínez-Klimova E. Hernández-Pando R. Sánchez- Lozada L.G. Pedraza-Chaverri J. Chronic impairment of mitochondrial bioenergetics and β-oxidation promotes experimental AKI-to-CKD transition induced by folic acid Free Radic. Biol. Med. 154 2020 18 32 10.1016/j.freeradbiomed.2020.04.016 32360615
62 Martínez-Klimova E. Aparicio-Trejo O.E. Gómez-Sierra T. Jiménez-Uribe A.P. Bellido B. Pedraza-Chaverri J. Mitochondrial dysfunction and endoplasmic reticulum stress in the promotion of fibrosis in obstructive nephropathy induced by unilateral ureteral obstruction Biofactors 46 2020 716 733 10.1002/biof.1673 32905648
63 Jiménez-Uribe A.P. Bellido B. Aparicio-Trejo O.E. Tapia E. Sánchez-Lozada L.G. Hernández-Santos J.A. Fernández-Valverde F. Hernández-Cruz E.Y. Orozco-Ibarra M. Pedraza-Chaverri J. Temporal characterization of mitochondrial impairment in the unilateral ureteral obstruction model in rats Free Radic. Biol. Med. 172 2021 358 371 10.1016/j.freeradbiomed.2021.06.019 34175439
64 Aparicio-Trejo O.E. Rojas-Morales P. Avila-Rojas S.H. León-Contreras J.C. Hernández-Pando R. Jiménez-Uribe A.P. Prieto-Carrasco R. Sánchez-Lozada L.G. Pedraza-Chaverri J. Tapia E. Temporal alterations in mitochondrial β-oxidation and oxidative stress aggravate chronic kidney disease development in 5/6 nephrectomy induced renal damage Int. J. Mol. Sci. 21 2020 1 19 10.3390/ijms21186512
65 Aparicio-Trejo O.E. Tapia E. Sánchez-Lozada L.G. Pedraza-Chaverri J. Mitochondrial bioenergetics, redox state, dynamics and turnover alterations in renal mass reduction models of chronic kidney diseases and their possible implications in the progression of this illness Pharmacol. Res. 135 2018 1 11 10.1016/j.phrs.2018.07.015 30030169
66 V Fedorova L. Tamirisa A. Kennedy D.J. Haller S.T. Budnyy G. Shapiro J.I. Malhotra D. Mitochondrial impairment in the five-sixth nephrectomy model of chronic renal failure: proteomic approach BMC Nephrol. 14 2013 209 230 10.1186/1471-2369-14-209 24090408
67 Afshinnia F. Rajendiran T.M. Soni T. Byun J. Wernisch S. Sas K.M. Hawkins J. Bellovich K. Gipson D. Michailidis G. Pennathur S. Impaired β -oxidation and altered complex lipid fatty acid partitioning with advancing CKD J. Am. Soc. Nephrol. 29 2018 295 306 10.1681/asn.2017030350 29021384
68 Duncan J.G. Mitochondrial dysfunction in diabetic cardiomyopathy Biochim. Biophys. Acta Mol. Cell Res. 1813 2011 1351 1359 10.1016/j.bbamcr.2011.01.014
69 Peoples J.N. Saraf A. Ghazal N. Pham T.T. Kwong J.Q. Mitochondrial dysfunction and oxidative stress in heart disease Exp. Mol. Med. 51 2019 10.1038/s12276-019-0355-7
70 Zhang Z. Sun M. Jiang W. Yu L. Zhang C. Ma H. Myocardial metabolic reprogramming in HFpEF J. Cardiovasc. Transl. Res. 17 2024 121 132 10.1007/s12265-023-10433-2 37650988
71 Munguia-Galaviz F.J. Gutierrez-Mercado Y.K. Miranda-Diaz A.G. Portilla de Buen E. Flores-Soto M.E. Echavarria R. Cardiac transcriptomic changes induced by early CKD in mice reveal novel pathways involved in the pathogenesis of Cardiorenal syndrome type 4 Heliyon 10 2024 e27468 10.1016/j.heliyon.2024.e27468
72 Huang Y. Wang S. Zhou J. Liu Y. Du C. Yang K. Bi X. Liu M. Han W. Wang K. Xiong J. Wang S. Wang Y. Nie L. Liu C. Zhang D. Gu J. Zeng C. Zhao J. IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4 Nat. Commun. 11 2020 4664 10.1038/s41467-020-18519-0 32938919
73 Tabei K. Levenson D.J. Brenner B.M. Early enhancement of fluid transport in rabbit proximal straight tubules after loss of contralateral renal excretory function J. Clin. Invest. 72 1983 871 881 10.1172/JCI111058 6886008
74 Welch W.J. Baumgärtl H. Lübbers D. Wilcox C.S. Nephron pO2 and renal oxygen usage in the hypertensive rat kidney Kidney Int. 59 2001 230 237 10.1046/j.1523-1755.2001.00483.x 11135075
75 Priyadarshi A. Periyasamy S. Burke T.J. Britton S.L. Malhotra D. Shapiro J.I. Effects of reduction of renal mass on renal oxygen tension and erythropoietin production in the rat Kidney Int. 61 2002 542 546 10.1046/j.1523-1755.2002.00140.x 11849394
76 Coughlan M.T. Nguyen T.-V. Penfold S.A. Higgins G.C. Thallas-Bonke V. Tan S.M. Van Bergen N.J. Sourris K.C. Harcourt B.E. Thorburn D.R. Trounce I.A. Cooper M.E. Forbes J.M. Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes Clin. Sci. 130 2016 711 720 10.1042/cs20150838
77 Forbes J.M. Thorburn D.R. Mitochondrial dysfunction in diabetic kidney disease Nat. Rev. Nephrol. 14 2018 291 312 10.1038/nrneph.2018.9 29456246
78 Liu J.J. Liu S. Gurung R.L. Ching J. Kovalik J.P. Tan T.Y. Lim S.C. Urine tricarboxylic acid cycle metabolites predict progressive chronic kidney disease in type 2 diabetes J. Clin. Endocrinol. Metab. 103 2018 4357 4364 10.1210/jc.2018-00947 30060124
79 Hallan S. Afkarian M. Zelnick L.R. Kestenbaum B. Sharma S. Saito R. Darshi M. Barding G. Raftery D. Ju W. Kretzler M. Sharma K. de Boer I.H. Metabolomics and gene expression analysis reveal down-regulation of the citric acid (TCA) cycle in non-diabetic CKD patients EBioMedicine 26 2017 68 77 10.1016/j.ebiom.2017.10.027 29128444
80 Li M. Wang X. Aa J. Qin W. Zha W. Ge Y. Liu L. Zheng T. Cao B. Shi J. Zhao C. Wang X. Yu X. Wang G. Liu Z. GC/TOFMS analysis of metabolites in serum and urine reveals metabolic perturbation of TCA cycle in db/db mice involved in diabetic nephropathy Am. J. Physiol. Ren. Physiol. 304 2013 1317 1324 10.1152/ajprenal.00536.2012
81 Liu H. Li W. He Q. Xue J. Wang J. Xiong C. Pu X. Nie Z. Mass spectrometry imaging of kidney tissue sections of rat subjected to unilateral ureteral obstruction Sci. Rep. 7 2017 1 9 10.1038/srep41954 28127051
82 Wei Q. Xiao X. Fogle P. Dong Z. Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion PLoS One 9 2014 1 13 10.1371/journal.pone.0106647
83 Aranda-Rivera A.K. Cruz-Gregorio A. Aparicio-Trejo O.E. Tapia E. Sánchez-Lozada L.G. García-Arroyo F.E. Amador-Martínez I. Orozco-Ibarra M. Fernández-Valverde F. Pedraza-Chaverri J. Sulforaphane protects against unilateral ureteral obstruction-induced renal damage in rats by alleviating mitochondrial and lipid metabolism impairment Antioxidants 11 2022 1854 10.3390/antiox11101854 36290577
84 Harzandi A. Lee S. Bidkhori G. Saha S. Hendry B.M. Mardinoglu A. Shoaie S. Sharpe C.C. Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia iScience 24 2021 102046 10.1016/j.isci.2021.102046
85 Tanada Y. Okuda J. Kato T. Minamino-Muta E. Murata I. Soga T. Shioi T. Kimura T. The metabolic profile of a rat model of chronic kidney disease PeerJ 2017 2017 1 19 10.7717/peerj.3352
86 Hallan S. Afkarian M. Zelnick L.R. Kestenbaum B. Sharma S. Saito R. Darshi M. Barding G. Raftery D. Ju W. Kretzler M. Sharma K. de Boer I.H. Metabolomics and gene expression analysis reveal down-regulation of the citric acid (TCA) cycle in non-diabetic CKD patients EBioMedicine 26 2017 68 77 10.1016/j.ebiom.2017.10.027 29128444
87 Kamarauskaite J. Baniene R. Trumbeckas D. Strazdauskas A. Trumbeckaite S. Increased succinate accumulation induces ROS generation in in vivo ischemia/reperfusion-affected rat kidney mitochondria BioMed Res. Int. 2020 2020 10.1155/2020/8855585
88 Jung I. Nam S. Lee D.Y. Park S.Y. Yu J.H. Seo J.A. Lee D.H. Kim N.H. Association of succinate and adenosine nucleotide metabolic pathways with diabetic kidney disease in patients with type 2 diabetes mellitus Diabetes Metab. J 2024 10.4093/dmj.2023.0377
89 Gullans S.R. Brazy P.C. Dennis V.W. Mandel L.J. Interactions between gluconeogenesis and sodium transport in rabbit proximal tubule Am. J. Physiol. 246 1984 F859 F869 10.1152/ajprenal.1984.246.6.F859 6331176
90 Gullans S.R. Kone B.C. Avison M.J. Giebisch G. Succinate alters respiration, membrane potential, and intracellular K+ in proximal tubule Am. J. Physiol. 255 1988 F1170 F1177 10.1152/ajprenal.1988.255.6.F1170 3202180
91 Robben J.H. Fenton R.A. Vargas S.L. Schweer H. Peti-Peterdi J. Deen P.M.T. Milligan G. Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells Kidney Int. 76 2009 1258 1267 10.1038/ki.2009.360 19776718
92 Lu Y.T. Li L.Z. Yang Y.L. Yin X. Liu Q. Zhang L. Liu K. Liu B. Li J. Qi L.W. Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling article Cell Death Dis. 9 2018 10.1038/s41419-018-0708-5
93 Toyohara T. Akiyama Y. Suzuki T. Takeuchi Y. Mishima E. Tanemoto M. Momose A. Toki N. Sato H. Nakayama M. Hozawa A. Tsuji I. Ito S. Soga T. Abe T. Metabolomic profiling of uremic solutes in CKD patients Hypertens. Res. 33 2010 944 952 10.1038/hr.2010.113 20613759
94 Sun H. Zhu G. Ling S. Liu J. Xu J.-W. 4’-O-methylbavachalcone inhibits succinate induced cardiomyocyte hypertrophy via the NFATc4 pathway Exp. Ther. Med. 25 2023 1 11 10.3892/etm.2023.11871 36561629
95 Li W. Quan L. Peng K. Wang Y. Wang X. Chen Q. Cheng H. Ma Q. Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts Basic Res. Cardiol. 118 2023 45 10.1007/s00395-023-01015-z 37819607
96 Aparicio-Trejo O.E. Tapia E. Molina-Jijón E. Medina-Campos O.N. Macías-Ruvalcaba N.A. León-Contreras J.C. Hernández-Pando R. García-Arroyo F.E. Cristóbal M. Sánchez-Lozada L.G. Pedraza-Chaverri J. Cristóbal M. Sánchez-Lozada L.G. Pedraza-Chaverri J. Curcumin prevents mitochondrial dynamics disturbances in early 5/6 nephrectomy: relation to oxidative stress and mitochondrial bioenergetics Biofactors 43 2017 293 310 10.1002/biof.1338 27801955
97 Ortega-Domínguez B. Aparicio-Trejo O.E. García-Arroyo F.E. León-Contreras J.C. Tapia E. Molina-Jijón E. Hernández-Pando R. Sánchez-Lozada L.G. Barrera-Oviedo D. Pedraza-Chaverri J. Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics and dynamic Food Chem. Toxicol. 107 2017 373 385 10.1016/j.fct.2017.07.018 28698153
98 Aparicio-Trejo O.E. Aranda-Rivera A.K. Osorio-Alonso H. Martínez-Klimova E. Sánchez-Lozada L.G. Pedraza-Chaverri J. Tapia E. Extracellular vesicles in redox signaling and metabolic regulation in chronic kidney disease Antioxidants 11 2022 356 10.3390/antiox11020356 35204238
99 Mailloux R.J. Protein S-glutathionylation reactions as a global inhibitor of cell metabolism for the desensitization of hydrogen peroxide signals Redox Biol. 32 2020 1 11 10.1016/j.redox.2020.101472
100 Prem P.N. Kurian G.A. High-Fat diet increased oxidative stress and mitochondrial dysfunction induced by renal ischemia-reperfusion injury in rat Front. Physiol. 12 2021 1 12 10.3389/fphys.2021.715693
101 Jedlička J. Grundmanová M. Švíglerová J. Tůma Z. Nalos L. Rajdl D. Štengl M. Kuncová J. Mitochondrial dysfunction in kidney cortex and medulla of subtotally nephrectomized rats Physiol. Res. 71 2022 S219 S226 10.33549/physiolres.935000 36647910
102 Lash L.H. Putt D.A. Horky S.J. Zalups R.K. Functional and toxicological characteristics of isolated renal mitochondria: impact of compensatory renal growth Biochem. Pharmacol. 62 2001 383 395 10.1016/S0006-2952(01)00673-6 11434913
103 Mohammad R.S. Lokhandwala M.F. Banday A.A. Age-Related Mitochondrial Impairment and Renal Injury Is Ameliorated by Sulforaphane via Activation of Transcription 2022
104 Aranda-Rivera A.K. Cruz-Gregorio A. Amador-Martínez I. Medina-Campos O.N. Garcia-Garcia M. Bernabe-Yepes B. León-Contreras J.C. Hernández-Pando R. Aparicio-Trejo O.E. Sánchez-Lozada L.G. Tapia E. Pedraza-Chaverri J. Sulforaphane protects from kidney damage during the release of unilateral ureteral obstruction (RUUO) by activating nuclear factor erythroid 2-related factor 2 (Nrf2): role of antioxidant, anti-inflammatory, and antiapoptotic mechanisms Free Radic. Biol. Med. 212 2024 49 64 10.1016/j.freeradbiomed.2023.12.022 38141891
105 Fohlen B. Tavernier Q. mum Huynh T. Caradeuc C. Le Corre D. Bertho G. Cholley B. Pallet N. Real-time and non-invasive monitoring of the activation of the ire1α-XBP1 pathway in individuals with hemodynamic impairment EBioMedicine 27 2018 284 292 10.1016/j.ebiom.2017.12.023 29276149
106 Thome T. Coleman M.D. Ryan T.E. Mitochondrial bioenergetic and proteomic phenotyping reveals organ-specific consequences of chronic kidney disease in mice Cells 10 2021 10.3390/cells10123282
107 Thome T. Salyers Z.R. Kumar R.A. Hahn D. Berru F.N. Ferreira L.F. Scali S.T. Ryan T.E. Uremic metabolites impair skeletal muscle mitochondrial energetics through disruption of the electron transport system and matrix dehydrogenase activity Am. J. Physiol. Cell Physiol. 317 2019 C701 C713 10.1152/ajpcell.00098.2019 31291144
108 Correa F. Buelna-Chontal M. Hernández-Reséndiz S. García-Niño W.R. Roldán F.J. Soto V. Silva-Palacios A. Amador A. Pedraza-Chaverrí J. Tapia E. Zazueta C. Curcumin maintains cardiac and mitochondrial function in chronic kidney disease Free Radic. Biol. Med. 61 2013 119 129 10.1016/j.freeradbiomed.2013.03.017 23548636
109 Guder W.G. Ross B.D. Enzyme distribution along the nephron Kidney Int. 26 1984 101 111 10.1038/ki.1984.143 6094907
110 Hansell P. Welch W.J. Blantz R.C. Palm F. Determinants of kidney oxygen consumption and their relationship to tissue oxygen tension in diabetes and hypertension Clin. Exp. Pharmacol. Physiol. 40 2013 123 137 10.1111/1440-1681.12034 23181475
111 Nath K.A. Croatt A.J. Hostetter T.H. Oxygen consumption and oxidant stress in surviving nephrons Am. J. Physiol. 258 1990 F1354 F1362 2337154
112 Thomas J.L. Pham H. Li Y. Hall E. Perkins G.A. Ali S.S. Patel H.H. Singh P. Hypoxia-inducible factor-1α activation improves renal oxygenation and mitochondrial function in early chronic kidney disease Am. J. Physiol. Ren. Physiol. 313 2017 F282 LP F290 10.1152/ajprenal.00579.2016
113 Chevalier R.L. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction Am. J. Physiol. Ren. Physiol. 311 2016 F145 F161 10.1152/ajprenal.00164.2016
114 Rabelink T.J. Carmeliet P. Renal metabolism in 2017: glycolytic adaptation and progression of kidney disease Nat. Rev. Nephrol. 14 2018 75 76 10.1038/nrneph.2017.173 29292369
115 Lan R. Geng H. Singha P.K. Saikumar P. Bottinger E.P. Weinberg J.M. Venkatachalam M.A. Mitochondrial pathology and glycolytic shift during proximal tubule atrophy after ischemic AKI J. Am. Soc. Nephrol. 27 2016 3356 3367 10.1681/ASN.2015020177 27000065
116 Ding H. Jiang L. Xu J. Bai F. Zhou Y. Yuan Q. Luo J. Zen K. Yang J. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis Am. J. Physiol. Ren. Physiol. 313 2017 F561 F575 10.1152/ajprenal.00036.2017
117 Wei Q. Su J. Dong G. Zhang M. Huo Y. Dong Z. Glycolysis inhibitors suppress renal interstitial fibrosis via divergent effects on fibroblasts and tubular cells Am. J. Physiol. Ren. Physiol. 316 2019 F1162 F1172 10.1152/ajprenal.00422.2018
118 Nakagawa T. Sanchez-Lozada L.G. Andres-Hernando A. Kojima H. Kasahara M. Rodriguez-Iturbe B. Bjornstad P. Lanaspa M.A. Johnson R.J. Endogenous fructose metabolism could explain the warburg effect and the protection of SGLT2 inhibitors in chronic kidney disease Front. Immunol. 12 2021 1 9 10.3389/fimmu.2021.694457
119 Lanaspa M.A. Ishimoto T. Cicerchi C. Tamura Y. Roncal-Jimenez C.A. Chen W. Tanabe K. Andres-Hernando A. Orlicky D.J. Finol E. Inaba S. Li N. Rivard C.J. Kosugi T. Sanchez-Lozada L.G. Petrash J.M. Sautin Y.Y. Ejaz A.A. Kitagawa W. Garcia G.E. Bonthron D.T. Asipu A. Diggle C.P. Rodriguez-Iturbe B. Nakagawa T. Johnson R.J. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy J. Am. Soc. Nephrol. 25 2014 2526 2538 10.1681/ASN.2013080901 24876114
120 Iskander C. Cherney D.Z. Clemens K.K. Dixon S.N. Harel Z. Jeyakumar N. McArthur E. Muanda F.T. Parikh C.R. Paterson J.M. Tangri N. Udell J.A. Wald R. Garg A.X. Use of sodium–glucose cotransporter-2 inhibitors and risk of acute kidney injury in older adults with diabetes: a population-based cohort study Can. Med. Assoc. J. 192 2020 E351 E360 10.1503/cmaj.191283 32392523
121 Taylor C.T. Scholz C.C. The effect of HIF on metabolism and immunity Nat. Rev. Nephrol. 18 2022 573 587 10.1038/s41581-022-00587-8 35726016
122 Basile D.P. Donohoe D. Roethe K. Osborn J.L. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function Am. J. Physiol. Ren. Physiol. 281 2001 887 899 10.1152/ajprenal.00050.2001
123 Bonello S. Zähringer C. BelAiba R.S. Djordjevic T. Hess J. Michiels C. Kietzmann T. Görlach A. Reactive oxygen species activate the HIF-1α promoter via a functional NFκB site Arterioscler. Thromb. Vasc. Biol. 27 2007 755 761 10.1161/01.ATV.0000258979.92828.bc 17272744
124 Iacobini C. Vitale M. Haxhi J. Pesce C. Pugliese G. Menini S. Mutual regulation between redox and hypoxia-inducible factors in cardiovascular and renal complications of diabetes Antioxidants 11 2022 1 22 10.3390/antiox11112183
125 Pagé E.L. Robitaille G.A. Pouysségur J. Richard D.E. Induction of hypoxia-inducible factor-1α by transcriptional and translational mechanisms J. Biol. Chem. 277 2002 48403 48409 10.1074/jbc.M209114200 12379645
126 Szeto H.H. Liu S. Soong Y. Seshan S.V. Cohen-Gould L. Manichev V. Feldman L.C. Gustafsson T. Mitochondria protection after acute ischemia prevents prolonged upregulation of IL-1 β and IL-18 and arrests CKD J. Am. Soc. Nephrol. 28 2017 1437 1449 10.1681/ASN.2016070761 27881606
127 Borges F.T. Melo S.A. Özdemir B.C. Kato N. Revuelta I. Miller C.A. Gattone V.H. LeBleu V.S. Kalluri R. TGF-β1-Containing exosomes from injured epithelial cells activate fibroblasts to initiate tissue regenerative responses and fibrosis J. Am. Soc. Nephrol. 24 2013 385 392 10.1681/ASN.2012101031 23274427
128 Zhang W. Zhou X. Yao Q. Liu Y. Zhang H. Dong Z. HIF-1-mediated production of exosomes during hypoxia is protective in renal tubular cells Am. J. Physiol. Ren. Physiol. 313 2017 F906 F913 10.1152/ajprenal.00178.2017
129 Göran Ronquist K. Extracellular vesicles and energy metabolism Clin. Chim. Acta 488 2019 116 121 10.1016/j.cca.2018.10.044 30395864
130 Zhang Y. Tan J. Miao Y. Zhang Q. The Effect of Extracellular Vesicles on the Regulation of Mitochondria under Hypoxia 2021 Springer US 10.1038/s41419-021-03640-9
131 Bodega G. Alique M. Puebla L. Carracedo J. Ramírez R.M. Microvesicles : ROS Scavengers and ROS Producers 8 2019
132 Li Z.L. Lv L.L. Tang T.T. Wang B. Feng Y. Zhou L.T. Cao J.Y. Tang R.N. Wu M. Liu H. Crowley S.D. Liu B.C. HIF-1α inducing exosomal microRNA-23a expression mediates the cross-talk between tubular epithelial cells and macrophages in tubulointerstitial inflammation Kidney Int. 95 2019 388 404 10.1016/j.kint.2018.09.013 30551896
133 Jella K.K. Yu L. Yue Q. Friedman D. Duke B.J. Alli A.A. Exosomal GAPDH from proximal tubule cells regulate ENaC activity PLoS One 11 2016 1 20 10.1371/journal.pone.0165763
134 Glider W.G. Schmidt U. The localization of gluconeogenesis in rat nephron: determination of phosphoenolpyruvate carboxykinase in microdissected tubules Hoppe. Seylers. Z. Physiol. Chem. 355 1974 273 278 10.1515/bchm2.1974.355.1.273 4435725
135 Meyer C. Stumvoll M. Dostou J. Welle S. Haymond M. Gerich J. Renal substrate exchange and gluconeogenesis in normal postabsorptive humans Am. J. Physiol. Endocrinol. Metab. 282 2002 428 434 10.1152/ajpendo.00116.2001
136 Schoolwerth A.C. Smith B.C. Culpepper R.M. Renal gluconeogenesis Miner. Electrolyte Metab. 14 1988 347 361 10.2337/diacare.24.2.382 3068502
137 Becker H.M. Mohebbi N. Perna A. Ganapathy V. Capasso G. Wagner C.A. Localization of members of MCT monocarboxylate transporter family Slc16 in the kidney and regulation during metabolic acidosis Am. J. Physiol. Ren. Physiol. 299 2010 141 154 10.1152/ajprenal.00488.2009
138 Tayek J.A. Katz J. Glucose production, recycling, and gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C] glucose study Am. J. Physiol. Endocrinol. Metab. 270 1996 10.1152/ajpendo.1996.270.4.e709
139 Bartlett S. Espinal J. Janssens P. Ross B.D. The influence of renal function on lactate and glucose metabolism Biochem. J. 219 1984 73 78 10.1042/bj2190073 6721865
140 Weidemann M.J. Krebs H.A. The fuel of respiration of rat kidney cortex Biochem. J. 112 1969 149 166 10.1042/bj1120149 5805283
141 Legouis D. Ricksten S.E. Faivre A. Verissimo T. Gariani K. Verney C. Galichon P. Berchtold L. Feraille E. Fernandez M. Placier S. Koppitch K. Hertig A. Martin P.Y. Naesens M. Pugin J. McMahon A.P. Cippà P.E. de Seigneux S. Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality Nat. Metab. 2 2020 732 743 10.1038/s42255-020-0238-1 32694833
142 Verissimo T. Faivre A. Rinaldi A. Lindenmeyer M. Delitsikou V. Veyrat-Durebex C. Heckenmeyer C. Fernandez M. Berchtold L. Dalga D. Cohen C. Naesens M. Ricksten S.-E. Martin P.-Y. Pugin J. Merlier F. Haupt K. Rutkowski J.M. Moll S. Cippà P.E. Legouis D. de Seigneux S. Decreased renal gluconeogenesis is a hallmark of chronic kidney disease J. Am. Soc. Nephrol. 33 2022 810 827 10.1681/ASN.2021050680 35273087
143 Doenst T. Nguyen T.D. Abel E.D. Cardiac metabolism in heart failure: implications beyond atp production Circ. Res. 113 2013 709 724 10.1161/CIRCRESAHA.113.300376 23989714
144 Yoganathan T. Perez-Liva M. Balvay D. Le Gall M. Lallemand A. Certain A. Autret G. Mokrani Y. Guillonneau F. Bruce J. Nguyen V. Gencer U. Schmitt A. Lager F. Guilbert T. Bruneval P. Vilar J. Maissa N. Mousseaux E. Viel T. Renault G. Kachenoura N. Tavitian B. Acute stress induces long-term metabolic, functional, and structural remodeling of the heart Nat. Commun. 14 2023 10.1038/s41467-023-39590-3
145 Kanbay M. Altıntas A. Yavuz F. Copur S. Sanchez-Lozada L.G. Lanaspa M.A. Johnson R.J. Responses to hypoxia: how fructose metabolism and hypoxia-inducible factor-1a pathways converge in health and disease Curr. Nutr. Rep. 12 2023 181 190 10.1007/s13668-023-00452-5 36708463
146 Kashihara T. Mukai R. Oka S.I. Zhai P. Nakada Y. Yang Z. Mizushima W. Nakahara T. Warren J.S. Abdellatif M. Sadoshima J. YAP mediates compensatory cardiac hypertrophy through aerobic glycolysis in response to pressure overload J. Clin. Invest. 132 2022 10.1172/JCI150595
147 Li Q. Li C. Elnwasany A. Sharma G. An Y.A. Zhang G. Elhelaly W.M. Lin J. Gong Y. Chen G. Wang M. Zhao S. Dai C. Smart C.D. Liu J. Luo X. Deng Y. Tan L. Lv S.J. Davidson S.M. Locasale J.W. Lorenzi P.L. Malloy C.R. Gillette T.G. Vander Heiden M.G. Scherer P.E. Szweda L.I. Fu G. Wang Z.V. PKM1 exerts critical roles in cardiac remodeling under pressure overload in the heart Circulation 144 2021 712 727 10.1161/CIRCULATIONAHA.121.054885 34102853
148 Kishi S. Nagasu H. Kidokoro K. Kashihara N. Oxidative stress and the role of redox signalling in chronic kidney disease Nat. Rev. Nephrol. 20 2023 10.1038/s41581-023-00775-0
149 Small D.M. Coombes J.S. Bennett N. Johnson D.W. Gobe G.C. Oxidative stress, anti-oxidant therapies and chronic kidney disease Nephrology 17 2012 311 321 10.1111/j.1440-1797.2012.01572.x 22288610
150 Sedeek M. Nasrallah R. Touyz R.M. Hébert R.L. NADPH oxidases, reactive oxygen species, and the kidney: friend and foe J. Am. Soc. Nephrol. 24 2013 1512 1518 10.1681/ASN.2012111112 23970124
151 Goligorsky M.S. Oxidative stress and the kidney: riding on the curve of hormesis, antioxid Redox Signal 25 2016 117 118 10.1089/ars.2016.6794
152 Sies H. Jones D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents Nat. Rev. Mol. Cell Biol. 21 2020 363 383 10.1038/s41580-020-0230-3 32231263
153 Mailloux R.J. Grayson C. Koufos O. Regulation of Mitochondrial Hydrogen Peroxide Availability by Protein S-Glutathionylation 2023
154 Lyublinskaya O. Antunes F. Redox Biology Measuring intracellular concentration of hydrogen peroxide with the use of genetically encoded H 2 O 2 biosensor HyPer Redox Biol. 24 2019 101200 10.1016/j.redox.2019.101200
155 Sies H. Jones D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents Nat. Rev. Mol. Cell Biol. 21 2020 363 383 10.1038/s41580-020-0230-3 32231263
156 Young A. Gill R. Mailloux R.J. Chemico-Biological Interactions Protein S-Glutathionylation : the Linchpin for the Transmission of Regulatory Information on Redox Bu Ff Ering Capacity in Mitochondria 299 2019 151 162 10.1016/j.cbi.2018.12.003
157 Holmström K.M. Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling Nat. Rev. Mol. Cell Biol. 15 2014 411 421 10.1038/nrm3801 24854789
158 Mailloux R.J. Willmore W.G. S-glutathionylation reactions in mitochondrial function and disease Front. Cell Dev. Biol. 2 2014 1 17 10.3389/fcell.2014.00068 25364710
159 Requejo R. Hurd T.R. Costa N.J. Murphy M.P. Cysteine residues exposed on protein surfaces are the dominant intramitochondrial thiol and may protect against oxidative damage FEBS J. 277 2010 1465 1480 10.1111/j.1742-4658.2010.07576.x 20148960
160 Mailloux R.J. Gill R. Young A. Protein S-glutathionylation and the regulation of cellular functions Oxidative Stress Eustress Distress 2019 Elsevier Inc. 217 247 10.1016/B978-0-12-818606-0.00013-4
161 Aquilano K. Baldelli S. Ciriolo M.R. Glutathione: new roles in redox signalling for an old antioxidant Front. Pharmacol. 5 AUG 2014 1 12 10.3389/fphar.2014.00196 24478702
162 Courtney-Martin G. Pencharz P.B. Sulfur amino acids metabolism from protein synthesis to glutathione Mol. Nutr. Amin. Acids Proteins A Vol. Mol. Nutr. Ser. 2016 265 286 10.1016/B978-0-12-802167-5.00019-0
163 Oestreicher J. Morgan B. Glutathione : subcellular distribution and membrane transport Biochem. Cell. Biol. 97 2019 270 289 10.1139/bcb-2018-0189 30427707
164 Morgan B. Ezeriņa D. Amoako T.N.E. Riemer J. Seedorf M. Dick T.P. Multiple glutathione disulfide removal pathways mediate cytosolic redox homeostasis Nat. Chem. Biol. 9 2013 119 125 10.1038/nchembio.1142 23242256
165 Griffith O.W. Meister A. Origin and turnover of mitochondrial glutathione Proc. Natl. Acad. Sci. U.S.A. 82 1985 4668 4672 10.1073/pnas.82.14.4668 3860816
166 Calabrese G. Morgan B. Riemer J. Mitochondrial glutathione: regulation and functions Antioxidants Redox Signal. 27 2017 1162 1177 10.1089/ars.2017.7121
167 Cummings B.S. Angeles R. McCauley R.B. Lash L.H. Role of voltage-dependent anion channels in glutathione transport into yeast mitochondria Biochem. Biophys. Res. Commun. 276 2000 940 944 10.1006/bbrc.2000.3572 11027572
168 Chen Z. Putt D.A. Lash L.H. Enrichment and functional reconstitution of glutathione transport activity from rabbit kidney mitochondria. Further evidence for the role of the dicarboxylate and 2-oxoglutarate carriers in mitochondrial glutathione transport Arch. Biochem. Biophys. 373 2000 193 202 10.1006/abbi.1999.1527 10620338
169 Schaedler T.A. Thornton J.D. Kruse I. Schwarzländer M. Meyer A.J. Van Veen H.W. Balk J. A conserved mitochondrial ATP-binding cassette transporter exports glutathione polysulfide for cytosolic metal cofactor assembly J. Biol. Chem. 289 2014 23264 23274 10.1074/jbc.M114.553438 25006243
170 Ribas V. García-Ruiz C. Fernández-Checa J.C. Glutathione and mitochondria Front. Pharmacol. 5 JUL 2014 1 19 10.3389/fphar.2014.00151 24478702
171 Fox J.T. Stover P.J. Folate-mediated one-carbon metabolism, vitam Horm. 79 2008 1 44 10.1016/S0083-6729(08)00401-9
172 W.E.Simpson E. Mitochondrial adenine malic dinucleotide bovine enzyme : adrenal the source for cortex of reduced steroid nicotinamide in phosphate hydroxylation mitochondria ’ chrome P-450 ( 19-23). The mixed function oxidases of adrenal cortex mitochondria utilize an Arch. Biochem. Biophys. 129 1969 384 395 4178715
173 Nickel A.G. Von Hardenberg A. Hohl M. Löffler J.R. Kohlhaas M. Becker J. Reil J.C. Kazakov A. Bonnekoh J. Stadelmaier M. Puhl S.L. Wagner M. Bogeski I. Cortassa S. Kappl R. Pasieka B. Lafontaine M. Lancaster C.R.D. Blacker T.S. Hall A.R. Duchen M.R. Kästner L. Lipp P. Zeller T. Müller C. Knopp A. Laufs U. Böhm M. Hoth M. Maack C. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure Cell Metabol. 22 2015 472 484 10.1016/j.cmet.2015.07.008
174 Francisco A. Figueira T.R. Castilho R.F. Mitochondrial NAD(P)+Transhydrogenase: from molecular features to physiology and disease Antioxidants Redox Signal. 36 2022 864 884 10.1089/ars.2021.0111
175 Bachhawat A.K. Thakur A. Kaur J. Zulkifli M. Glutathione transporters Biochim. Biophys. Acta Gen. Subj. 1830 2013 3154 3164 10.1016/j.bbagen.2012.11.018
176 Richman P.G. Meister A. Regulation of γ glutamyl cysteine synthetase by nonallosteric feedback inhibition by glutathione J. Biol. Chem. 250 1975 1422 1426 10.1016/s0021-9258(19)41830-9 1112810
177 Chen Y. Shertzer H.G. Schneider S.N. Nebert D.W. Dalton T.P. Glutamate cysteine ligase catalysis: dependence on ATP and modifier subunit for regulation of tissue glutathione levels J. Biol. Chem. 280 2005 33766 33774 10.1074/jbc.M504604200 16081425
178 Backos D.S. Fritz K.S. McArthur D.G. Kepa J.K. Donson A.M. Petersen D.R. Foreman N.K. Franklin C.C. Reigan P. Glycation of glutamate cysteine ligase by 2-deoxy-d-ribose and its potential impact on chemoresistance in glioblastoma Neurochem. Res. 38 2013 1838 1849 10.1007/s11064-013-1090-4 23743623
179 Sun W.M. Huang Z.Z. Lu S.C. Regulation of γ-glutamylcysteine synthetase by protein phosphorylation Biochem. J. 320 1996 321 328 10.1042/bj3200321 8947504
180 Gipp J.J. Bailey H.H. Mulcahy R.T. Cloning and sequencing of the cDNA for the light subunit of human liver γ-glutamylcysteine synthetase and relative RNA levels for heavy and light subunits in human normal tissues Biochem. Biophys. Res. Commun. 206 1995 584 589 10.1006/bbrc.1995.1083 7826375
181 Kong A.N.T. Owuor E. Yu R. Hebbar V. Chen C. Hu R. Mandlekar S. Induction of xenobiotic enzymes by the map kinase pathway and the antioxidant or electrophile response element (ARE/EpRE) Drug Metab. Rev. 33 2001 255 271 10.1081/DMR-120000652 11768769
182 Moran J.A. Dahl E.L. Mulcahy R.T. Differential induction of maff, mafg and mafk expression by electrophile-response-element activators Biochem. J. 361 2002 371 377 10.1042/0264-6021:3610371 11772409
183 Venugopal R. Jaiswal A.K. Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes Oncogene 17 1998 3145 3156 10.1038/sj.onc.1202237 9872330
184 Meng Q. Peng Z. Chen L. Si J. Dong Z. Xia Y. Nuclear Factor-κB modulates cellular glutathione and prevents oxidative stress in cancer cells Cancer Lett. 299 2010 45 53 10.1016/j.canlet.2010.08.002 20810208
185 Aquilano K. Baldelli S. Ciriolo M.R. Glutathione: new roles in redox signalling for an old antioxidant Front. Pharmacol. 5 AUG 2014 1 12 10.3389/fphar.2014.00196 24478702
186 Lash L.H. Role of glutathione transport processes in kidney function Toxicol. Appl. Pharmacol. 204 2005 329 342 10.1016/j.taap.2004.10.004 15845422
187 Lash L.H. Putt D.A. Renal cellular transport of exogenous glutathione: heterogeneity at physiological and pharmacological concentrations Biochem. Pharmacol. 58 1999 897 907 10.1016/S0006-2952(99)00155-0 10449202
188 Hinchman C.A. Ballatori N. Glutathione-degrading capacities of liver and kidney in different species Biochem. Pharmacol. 40 1990 1131 1135 10.1016/0006-2952(90)90503-D 1975172
189 Fernández E. Carrascal M. Rousaud F. Abián J. Zorzano A. Palacín M. Chillarón J. rBAT-b 0,+ AT heterodimer is the main apical reabsorption system for cystine in the kidney Am. J. Physiol. Physiol. 283 2002 F540 F548 10.1152/ajprenal.00071.2002
190 Cole S.P.C. Multidrug resistance protein 1 (mrp1, abcc1), a “multitasking” atp-binding cassette (abc,) transporter J. Biol. Chem. 289 2014 30880 30888 10.1074/jbc.R114.609248 25281745
191 Lash L.H. Renal membrane transport of glutathione in toxicology and disease Vet. Pathol. 48 2011 408 419 10.1177/0300985810375811 20656901
192 Mohandas J. Marshall J.J. Duggin G.G. Horvath J.S. Tiller D.J. Differential distribution of glutathione and glutathione-related enzymes in rabbit kidney. Possible implications in analgesic nephropathy Biochem. Pharmacol. 33 1984 1801 1807 10.1016/0006-2952(84)90353-8 6145422
193 Parks L.D. Zalups R.K. Barfuss D.W. Heterogeneity of glutathione synthesis and secretion in the proximal tubule of the rabbit Am. J. Physiol. Ren. Physiol. 274 1998 924 931 10.1152/ajprenal.1998.274.5.f924
194 Duncan J.G. Mitochondrial dysfunction in diabetic cardiomyopathy Biochim. Biophys. Acta Mol. Cell Res. 1813 2011 1351 1359 10.1016/j.bbamcr.2011.01.014
195 Peoples J.N. Saraf A. Ghazal N. Pham T.T. Kwong J.Q. Mitochondrial dysfunction and oxidative stress in heart disease Exp. Mol. Med. 51 2019 10.1038/s12276-019-0355-7
196 Chen Y. Saari J.T. Kang Y.J. Weak antioxidant defenses make the heart a target for damage in copper-deficient rats Free Radic. Biol. Med. 17 1994 529 536 10.1016/0891-5849(94)90092-2 7867969
197 Ishikawa T. Sies H. Cardiac transport of glutathione disulfide and S-conjugate. Studies with isolated perfused rat heart during hydroperoxide metabolism J. Biol. Chem. 259 1984 3838 3843 10.1016/s0021-9258(17)43173-5 6706982
198 Li S. Li X. Rozanski G.J. Regulation of glutathione in cardiac myocytes J. Mol. Cell. Cardiol. 35 2003 1145 1152 10.1016/S0022-2828(03)00230-X 12967637
199 Punekar N.S. Is there an inter-organ glutathione redox cycle? Indian J. Biochem. Biophys. 28 1991 496 498 1812088
200 Tan M. Yin Y. Ma X. Zhang J. Pan W. Tan M. Zhao Y. Yang T. Jiang T. Li H. Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis Cell Death Dis. 14 2023 10.1038/s41419-023-05645-y
201 Jungsuwadee P. Cole M.P. Sultana R. Joshi G. Tangpong J. Butterfield D.A. Clair D.K. St Vore M. Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice Mol. Cancer Therapeut. 5 2006 2851 2860 10.1158/1535-7163.MCT-06-0297
202 Matuz-Mares D. Riveros-Rosas H. Vázquez-Meza H. Vilchis-Landeros M.M. Glutathione participation in the prevention of cardiovascular diseases Antioxidants 10 2021 10.3390/antiox10081220
203 Jang S. Chapa-Dubocq X.R. Tyurina Y.Y. St Croix C.M. Kapralov A.A. Tyurin V.A. Bayır H. Kagan V.E. Javadov S. Elucidating the contribution of mitochondrial glutathione to ferroptosis in cardiomyocytes Redox Biol. 45 2021 102021 10.1016/j.redox.2021.102021
204 Bachhawat A.K. Kaur A. Glutathione degradation Antioxidants Redox Signal. 27 2017 1200 1216 10.1089/ars.2017.7136
205 Kumar A. Tikoo S. Maity S. Sengupta S. Sengupta S. Kaur A. Bachhawat A.K. Mammalian proapoptotic factor ChaC1 and its homologues function as γ-glutamyl cyclotransferases acting specifically on glutathione EMBO Rep. 13 2012 1095 1101 10.1038/embor.2012.156 23070364
206 Bachhawat A.K. Yadav S. Jainarayanan A.K. Dubey P. Heart failure and the glutathione cycle: an integrated view Biochem. J. 477 2020 3123 3130 10.1042/bcj20200429 32886767
207 Kitakata H. Endo J. Matsushima H. Yamamoto S. Ikura H. Hirai A. Koh S. Ichihara G. Hiraide T. Moriyama H. Shirakawa K. Goto S. Katsumata Y. Anzai A. Kataoka M. Tokuyama T. Ishido S. Yanagi S. Fukuda K. Sano M. MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis J. Mol. Cell. Cardiol. 161 2021 116 129 10.1016/j.yjmcc.2021.08.006 34390730
208 Wang X. Chen X. Zhou W. Men H. Bao T. Sun Y. Wang Q. Tan Y. Keller B.B. Tong Q. Zheng Y. Cai L. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways Acta Pharm. Sin. B 12 2022 708 722 10.1016/j.apsb.2021.10.005 35256941
209 Kumar P. Osahon O.W. Sekhar R.V. GlyNAC (Glycine and N-acetylcysteine) supplementation in mice increases length of life by correcting glutathione deficiency, oxidative stress, mitochondrial dysfunction, abnormalities in mitophagy and nutrient sensing, and genomic damage Nutrients 14 2022 10.3390/nu14051114
210 Wang X. Chen X. Zhou W. Men H. Bao T. Sun Y. Wang Q. Tan Y. Keller B.B. Tong Q. Zheng Y. Cai L. Ferroptosis is essential for diabetic cardiomyopathy and is prevented by sulforaphane via AMPK/NRF2 pathways Acta Pharm. Sin. B 12 2022 708 722 10.1016/j.apsb.2021.10.005 35256941
211 Ortega-Domínguez B. Aparicio-Trejo O.E. García-Arroyo F.E. León-Contreras J.C. Tapia E. Molina-Jijón E. Hernández-Pando R. Sánchez-Lozada L.G. Barrera-Oviedo D. Pedraza-Chaverri J. Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics and dynamic Food Chem. Toxicol. 107 2017 373 385 10.1016/j.fct.2017.07.018 28698153
212 Hernández-Reséndiz S. Correa F. García-Niño W.R. Buelna-Chontal M. Roldán F.J. Ramírez-Camacho I. Delgado-Toral C. Carbó R. Pedraza-Chaverrí J. Tapia E. Zazueta C. Cardioprotection by curcumin post-treatment in rats with established chronic kidney disease, cardiovasc Drug Ther. 29 2015 111 120 10.1007/s10557-015-6581-x
213 Chai Y.C. Mieyal J.J. Glutathione and glutaredoxin—key players in cellular redox homeostasis and signaling Antioxidants 12 2023 1 15 10.3390/antiox12081553
214 Ergin B. Guerci P. Zafrani L. Nocken F. Kandil A. Gurel-Gurevin E. Demirci-Tansel C. Ince C. Effects of N-acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia Intensive Care Med. Exp. . 4 2016 1 17 10.1186/s40635-016-0106-1 26738486
215 Shimizu M.H.M. Gois P.H.F. Volpini R.A. Canale D. Luchi W.M. Froeder L. Heilberg I.P. Seguro A.C. N-acetylcysteine protects against star fruit-induced acute kidney injury Ren. Fail. 39 2017 193 202 10.1080/0886022X.2016.1256315 27845599
216 Shen Y. Miao N.J. Xu J.L. Gan X.X. Xu D. Zhou L. Xue H. Zhang W. Lu L.M. N-acetylcysteine alleviates angiotensin II-mediated renal fibrosis in mouse obstructed kidneys Acta Pharmacol. Sin. 37 2016 637 644 10.1038/aps.2016.12 27041464
217 Ware K. Qamri Z. Ozcan A. Satoskar A.A. Nadasdy G. Rovin B.H. Hebert L.A. Nadasdy T. Brodsky S.V. N-acetylcysteine ameliorates acute kidney injury but not glomerular hemorrhage in an animal model of warfarin-related nephropathy Am. J. Physiol. Ren. Physiol. 304 2013 1421 1427 10.1152/ajprenal.00689.2012
218 Kizilgun M. Poyrazoglu Y. Oztas Y. Yaman H. Cakir E. Cayci T. Akgul O.E. Kurt Y.G. Yaren H. Kunak Z.I. MacIt E. Ozkan E. Taslipinar M.Y. Turker T. Ozcan A. Beneficial effects of N-acetylcysteine and ebselen on renal Ischemia/reperfusion injury Ren. Fail. 33 2011 512 517 10.3109/0886022X.2011.574767 21545313
219 Camuglia A.C. Maeder M.T. Starr J. Farrington C. Kaye D.M. Impact of N-acetylcysteine on endothelial function, B-type natriuretic peptide and renal function in patients with the cardiorenal syndrome: a pilot cross over randomised controlled trial Heart Lung Circ. 22 2013 256 259 10.1016/j.hlc.2012.10.012 23219310
220 Giam B. Kuruppu S. Chu P.Y. Smith A.I. Marques F.Z. Fiedler A. Horlock D. Kiriazis H. Du X.J. Kaye D.M. Rajapakse N.W. N-acetylcysteine attenuates the development of renal fibrosis in transgenic mice with dilated cardiomyopathy Sci. Rep. 7 2017 1 12 10.1038/s41598-017-17927-5 28127051
221 Khan S.A. Campbell A.M. Lu Y. An L. Alpert J.S. Chen Q.M. N-acetylcysteine for cardiac protection during coronary artery reperfusion: a systematic review and meta-analysis of randomized controlled trials Front. Cardiovasc. Med. 8 2021 10.3389/fcvm.2021.752939
222 Pedre B. Barayeu U. Ezeriņa D. Dick T.P. The mechanism of action of N-acetylcysteine (NAC): the emerging role of H2S and sulfane sulfur species Pharmacol. Ther. 228 2021 10.1016/j.pharmthera.2021.107916
223 Pereira L.V.B. Shimizu M.H.M. Rodrigues L.P.M.R. Leite C.C. Andrade L. Seguro A.C. N-Acetylcysteine protects rats with chronic renal failure from gadolinium-chelate nephrotoxicity PLoS One 7 2012 1 5 10.1371/journal.pone.0039528
224 Hanly L. Figueredo R. Rieder M.J. Koropatnick J. Koren G. The effects of N-acetylcysteine on ifosfamide efficacy in a mouse xenograft model Anticancer Res. 32 2012 3791 3798 22993321
225 Machado J.T. Iborra R.T. Fusco F.B. Castilho G. Pinto R.S. Machado-Lima A. Nakandakare E.R. Seguro A.C. Shimizu M.H. Catanozi S. Passarelli M. N-acetylcysteine prevents endoplasmic reticulum stress elicited in macrophages by serum albumin drawn from chronic kidney disease rats and selectively affects lipid transporters, ABCA-1 and ABCG-1 Atherosclerosis 237 2014 343 352 10.1016/j.atherosclerosis.2014.09.020 25305669
226 Ware K.M. Vance J.C. Muni N. Hebert L.A. Satoskar A.A. Nadasdy G. Ivanov I. Nadasdy T. Rovin B.H. Brodsky S.V. Oral warfarin and the thrombin inhibitor dabigatran increase blood pressure in rats: hidden danger of anticoagulants? Am. J. Hypertens. 28 2015 182 189 10.1093/ajh/hpu129 25023204
227 Mohamed N.A. Hassan M.H. Saleem T.H. Mohamed S.A. El-Zeftawy M. Ahmed E.A. Mostafa N.A.M. Hetta H.F. Al Shaimaa H. Abdallah A.A.M. KIM-1 and GADDI-153 gene expression in paracetamol-induced acute kidney injury: effects of N-acetylcysteine, N-acetylmethionine, and N-acetylglucosamine Turk. J. Biochem. 47 2022 409 416 10.1515/tjb-2021-0233
228 Song L. Yao S. Zheng D. Xuan Y. Li W. Astaxanthin attenuates contrast-induced acute kidney injury in rats via ROS/NLRP3 inflammasome Int. Urol. Nephrol. 54 2022 1355 1364 10.1007/s11255-021-03015-1 34652584
229 Gu Y. Huang F. Wang Y. Chen C. Wu S. Zhou S. Hei Z. Yuan D. Connexin32 plays a crucial role in ROS-mediated endoplasmic reticulum stress apoptosis signaling pathway in ischemia reperfusion-induced acute kidney injury J. Transl. Med. 16 2018 1 13 10.1186/s12967-018-1493-8 29316942
230 Dong W. Zhang K. Gong Z. Luo T. Li J. Wang X. Zou H. Song R. Zhu J. Ma Y. Liu G. Liu Z. N-acetylcysteine delayed cadmium-induced chronic kidney injury by activating the sirtuin 1–P53 signaling pathway Chem. Biol. Interact. 369 2023 110299 10.1016/j.cbi.2022.110299
231 Gong X. Duan Y. Zheng J. Wang Y. Wang G. Norgren S. Hei T.K. Nephroprotective effects of N-acetylcysteine amide against contrast-induced nephropathy through upregulating thioredoxin-1, inhibiting ASK1/p38MAPK pathway, and suppressing oxidative stress and apoptosis in rats Oxid. Med. Cell. Longev. 2016 2016 10.1155/2016/8715185
232 Huang S. You J. Wang K. Li Y. Zhang Y. Wei H. Liang X. Liu Y. N -acetylcysteine attenuates cisplatin-induced acute kidney injury by inhibiting the C5a receptor BioMed Res. Int. 2019 2019 10.1155/2019/4805853
233 Lee J.H. Jo Y.H. Kim K. Lee J.H. Rim K.P. Kwon W.Y. Suh G.J. Rhee J.E. Effect of N-acetylcysteine (NAC) on acute lung injury and acute kidney injury in hemorrhagic shock Resuscitation 84 2013 121 127 10.1016/j.resuscitation.2012.05.017 22664745
234 Ali Abdelrazik Eman Hassan Hend Mohammed Mohammed Abdallah Mahmoud Zienab Yousef Alshimaa Magdy Elsayed Eman Abdo Renoprotective effect of N-acetylcystein and vitamin E in bisphenol A-induced rat nephrotoxicity; Modulators of Nrf2/NF-κB and ROS signaling pathway Acta Biomed. 93 2022 e2022301 10.23750/abm.v93i6.13732
235 Wang S. Liu G. Jia T. Wang C. Lu X. Tian L. Yang Q. Zhu C. Protection against post-resuscitation acute kidney injury by N-acetylcysteine via activation of the Nrf2/HO-1 pathway Front. Med. 9 2022 1 16 10.3389/fmed.2022.848491
236 Li C. Xie N. Li Y. Liu C. Hou F.F. Wang J. N-acetylcysteine ameliorates cisplatin-induced renal senescence and renal interstitial fibrosis through sirtuin1 activation and p53 deacetylation Free Radic. Biol. Med. 130 2019 512 527 10.1016/j.freeradbiomed.2018.11.006 30447351
237 Liu C. Shen Y. Huang L. Wang J. TLR2/caspase-5/Panx1 pathway mediates necrosis-induced NLRP3 inflammasome activation in macrophages during acute kidney injury Cell Death Dis. 8 2022 1 13 10.1038/s41420-022-01032-2
238 Volgers C. Benedikter B.J. Grauls G.E. Hellebrand H.M. Savelkoul P.H.M. Stassen F.R.M. Effects of N-acetyl-L-cysteine on the membrane vesicle release and growth of respiratory pathogens FEMS Microbiol. Lett. 364 2017 1 8 10.1093/femsle/fnx087
239 Molina-Jijón E. Aparicio-Trejo O.E. Rodríguez-Muñoz R. León-Contreras J.C. del Carmen Cárdenas-Aguayo M. Medina-Campos O.N. Tapia E. Sánchez-Lozada L.G. Hernández-Pando R. Reyes J.L. Arreola-Mendoza L. Pedraza-Chaverri J. The nephroprotection exerted by curcumin in maleate-induced renal damage is associated with decreased mitochondrial fission and autophagy Biofactors 42 2016 686 702 10.1002/biof.1313 27412471
240 Mao H. Zhang Y. Xiong Y. Zhu Z. Wang L. Liu X. Mitochondria-targeted antioxidant mitoquinone maintains mitochondrial homeostasis through the sirt3-dependent pathway to mitigate oxidative damage caused by renal ischemia/reperfusion Oxid. Med. Cell. Longev. 2022 2022 10.1155/2022/2213503
241 Zhu M. He J. Xu Y. Zuo Y. Zhou W. Yue Z. Shao X. Cheng J. Wang T. Mou S. AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury Mol. Ther. 31 2023 3052 3066 10.1016/j.ymthe.2023.08.014 37608549
242 Mukhopadhyay P. Horváth B. Zsengellér Z. Zielonka J. Tanchian G. Holovac E. Kechrid M. Patel V. Stillman I.E. Parikh S.M. Joseph J. Kalyanaraman B. Pacher P. Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy Free Radic. Biol. Med. 52 2012 497 506 10.1016/j.freeradbiomed.2011.11.001 22120494
243 Gottwald E.M. Duss M. Bugarski M. Haenni D. Schuh C.D. Landau E.M. Hall A.M. The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue Phys. Rep. 6 2018 1 9 10.14814/phy2.13667
244 Zinovkin R.A. Lyamzaev K.G. Chernyak B.V. Current perspectives of mitochondria-targeted antioxidants in cancer prevention and treatment Front. Cell Dev. Biol. 11 2023 1 15 10.3389/fcell.2023.1048177
245 Wang Z. Fu Y. da Silva A.A. do Carmo J.M. Mouton A. Omoto A.C.M. Li X. Sears J. Hall J.E. Mitochondria-derived reactive oxygen species contribute to synergistic interaction of diabetes and hypertension in causing chronic kidney injury Am. J. Physiol. Ren. Physiol. 326 2024 F534 F544 10.1152/ajprenal.00320.2023
246 Miyamoto S. Zhang G. Hall D. Oates P.J. Maity S. Madesh M. Han X. Sharma K. Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db/db mice against progression of diabetic kidney disease J. Biol. Chem. 295 2020 7249 7260 10.1074/jbc.RA119.011110 32277051
247 Daubert M.A. Yow E. Dunn G. Marchev S. Barnhart H. Douglas P.S. O'Connor C. Goldstein S. Udelson J.E. Sabbah H.N. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide Circ. Hear. Fail. 10 2017 1 12 10.1161/CIRCHEARTFAILURE.117.004389
248 Saad A. Herrmann S.M.S. Eirin A. Ferguson C.M. Glockner J.F. Bjarnason H. McKusick M.A. Misra S. Lerman L.O. Textor S.C. Phase 2a clinical trial of mitochondrial protection (elamipretide) during stent revascularization in patients with atherosclerotic renal artery stenosis, circ Cardiovasc. Interv. 10 2017 1 8 10.1161/CIRCINTERVENTIONS.117.005487
249 Liu B. Chen L. Gao M. Dai M. Zheng Y. Qu L. Zhang J. Gong G. A comparative study of the efficiency of mitochondria-targeted antioxidants MitoTEMPO and SKQ1 under oxidative stress Free Radic. Biol. Med. 224 2024 117 129 10.1016/j.freeradbiomed.2024.08.022 39178922
250 Song J. Sheng J. Lei J. Gan W. Yang Y. Mitochondrial targeted antioxidant SKQ1 ameliorates acute kidney injury by inhibiting ferroptosis Oxid. Med. Cell. Longev. 2022 2022 2223957 10.1155/2022/2223957
251 Zhang Y.-B. Meng Y.-H. Chang S. Zhang R.-Y. Shi C. High fructose causes cardiac hypertrophy via mitochondrial signaling pathway Am. J. Transl. Res. 8 2016 4869 4880 27904687
252 Tovar-Palacio C. Noriega L.G. Mercado A. Potential of polyphenols to restore SIRT1 and NAD+ metabolism in renal disease Nutrients 14 2022 1 33 10.3390/nu14030653
253 Reyes-Fermín L.M. Avila-Rojas S.H. Aparicio-Trejo O.E. Tapia E. Rivero I. Pedraza-Chaverri J. The protective effect of alpha-mangostin against cisplatin-induced cell death in LLC-PK1 cells is associated to mitochondrial function preservation Antioxidants 8 2019 133 10.3390/antiox8050133 31096625
254 Sato Y. Yanagita M. Immune cells and inflammation in AKI to CKD progression Am. J. Physiol. Ren. Physiol. 315 2018 F1501 F1512 10.1152/ajprenal.00195.2018
255 Liu Y. Cellular and molecular mechanisms of renal fibrosis Nat. Rev. Nephrol. 7 2011 684 696 10.1038/nrneph.2011.149 22009250
256 Martínez-Klimova E. Aparicio-Trejo O.E. Tapia E. Pedraza-Chaverri J. Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments Biomolecules 9 2019 1 29 10.3390/biom9040141
257 Srivastava S.P. Kanasaki K. Goodwin J.E. Loss of mitochondrial control impacts renal health Front. Pharmacol. 11 2020 1 19 10.3389/fphar.2020.543973 32116689
258 Andrade-Oliveira V. Foresto-Neto O. Watanabe I.K.M. Zatz R. Câmara N.O.S. Inflammation in renal diseases: new and old players Front. Pharmacol. 10 2019 1 19 10.3389/fphar.2019.01192 30728774
259 Swanson K.V. Deng M. Ting J.P.Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics Nat. Rev. Immunol. 19 2019 477 489 10.1038/s41577-019-0165-0 31036962
260 Zhang Q. Raoof M. Chen Y. Sumi Y. Sursal T. Junger W. Brohi K. Itagaki K. Hauser C.J. Circulating mitochondrial DAMPs cause inflammatory responses to injury Nature 464 2010 104 107 10.1038/nature08780 20203610
261 Wallace K.B. Adriamycin-induced Interference with Cardiac Mitochondrial Calcium Homeostasis 2007 101 107 10.1007/s12012-007-0008-2
262 Thom S.R. Bhopale V.M. Hu J.P. Yang M. Increased carbon dioxide levels stimulate neutrophils to produce microparticles and activate the nucleotide-binding domain-like receptor 3 inflammasome Free Radic. Biol. Med. 106 2017 406 416 10.1016/j.freeradbiomed.2017.03.005 28288918
263 Li G. Huang D. Li N. Ritter J.K. Li P.L. Regulation of TRPML1 channel activity and inflammatory exosome release by endogenously produced reactive oxygen species in mouse podocytes Redox Biol. 43 2021 1 11 10.1016/j.redox.2021.102013
264 Dominguez J.H. Xie D. Kelly K.J. Cardiac effects of renal ischemia Am. J. Physiol. Ren. Physiol. 324 2023 F64 F72 10.1152/ajprenal.00183.2022
265 Prud’homme M. Coutrot M. Michel T. Boutin L. Genest M. Poirier F. Launay J.M. Kane B. Kinugasa S. Prakoura N. Vandermeersch S. Cohen-Solal A. Delcayre C. Samuel J.L. Mehta R. Gayat E. Mebazaa A. Chadjichristos C.E. Legrand M. Acute kidney injury induces remote cardiac damage and dysfunction through the galectin-3 pathway, JACC basic to transl Science 4 2019 717 732 10.1016/j.jacbts.2019.06.005
266 Panico K. Abrahão M.V. Trentin-Sonoda M. Muzi-Filho H. Vieyra A. Carneiro-Ramos M.S. Cardiac inflammation after ischemia-reperfusion of the kidney: role of the sympathetic nervous system and the renin-angiotensin system Cell. Physiol. Biochem. 53 2019 587 605 10.33594/000000159 31535830
267 Viswanadha V.P. Dhivya V. Beeraka N.M. Huang C.Y. Gavryushova L.V. Minyaeva N.N. Chubarev V.N. Mikhaleva L.M. Tarasov V.V. Aliev G. The protective effect of piperine against isoproterenol-induced inflammation in experimental models of myocardial toxicity Eur. J. Pharmacol. 885 2020 173524 10.1016/j.ejphar.2020.173524
268 Liu H. Zhang Y. Wu Z. Zhang L. Identification of IL-6 as a potential mediator of the myocardial fibrosis that occurs in response to surgery with cardiopulmonary bypass in children with Tetralogy of Fallot Cardiol. Young 32 2022 223 229 10.1017/S1047951121001803 34134814
269 Wang Y.Y. Yang C. Wang Z. Wang Y.Y. Yan Q. Feng Y. Liu Y. Huang J. Zhou J. Epithelial galectin-3 induced the mitochondrial complex inhibition and cell cycle arrest of CD8+ T cells in severe/critical COVID-19 Int. J. Mol. Sci. 24 2023 10.3390/ijms241612780
270 Wang J. Sun X. Wang X. Cui S. Liu R. Liu J. Fu B. Gong M. Wang C. Shi Y. Chen Q. Cai G. Chen X. Grb2 induces cardiorenal syndrome type 3: roles of IL-6, cardiomyocyte bioenergetics, and akt/mTOR pathway Front. Cell Dev. Biol. 9 2021 1 15 10.3389/fcell.2021.630412
271 Lillo-Moya J. Rojas-Solé C. Muñoz-Salamanca D. Panieri E. Saso L. Rodrigo R. Targeting ferroptosis against ischemia/reperfusion cardiac injury Antioxidants 10 2021 1 25 10.3390/antiox10050667
272 Junho C.V.C. González-Lafuente L. Neres-Santos R.S. Navarro-García J.A. Rodríguez-Sánchez E. Ruiz-Hurtado G. Carneiro-Ramos M.S. Klotho relieves inflammation and exerts a cardioprotective effect during renal ischemia/reperfusion-induced cardiorenal syndrome Biomed. Pharmacother. 153 2022 10.1016/j.biopha.2022.113515
273 Wen Y. Liu Y.R. Tang T.T. Pan M.M. Xu S.C. Ma K.L. Lv L.L. Liu H. Liu B.C. mROS-TXNIP axis activates NLRP3 inflammasome to mediate renal injury during ischemic AKI Int. J. Biochem. Cell Biol. 98 2018 43 53 10.1016/j.biocel.2018.02.015 29477360
274 Zeng H. Zou P. Chen Y. Zhang P. Shao L. NOX4 aggravates doxorubicin-induced cardiomyocyte pyroptosis by increasing reactive oxygen species content and activating the NLRP3 inflammasome Cardiovasc. Diagn. Ther. 14 2024 84 100 10.21037/cdt-23-142 38434559
275 Kim S.M. Kim Y.G. Kim D.J. Park S.H. Jeong K.H. Lee Y.H. Lim S.J. Lee S.H. Moon J.Y. Inflammasome-independent role of NLRP3 mediates mitochondrial regulation in renal injury Front. Immunol. 9 2018 1 14 10.3389/fimmu.2018.02563 29403488
276 Ouyang J. Zeng Z. Fang H. Li F. Zhang X. Tan W. SIRT3 inactivation promotes acute kidney injury through elevated acetylation of SOD2 and p53 J. Surg. Res. 233 2019 221 230 10.1016/j.jss.2018.07.019 30502252
277 Sanz-Ros J. Mas-Bargues C. Romero-García N. Huete-Acevedo J. Dromant M. Borrás C. The potential use of mitochondrial extracellular vesicles as biomarkers or therapeutical tools Int. J. Mol. Sci. 24 2023 10.3390/ijms24087005
278 Han W. Du C. Zhu Y. Ran L. Wang Y. Xiong J. Wu Y. Lan Q. Wang Y. Wang L. Wang J. Yang K. Zhao J. Targeting myocardial mitochondria-STING-polyamine Axis prevents cardiac hypertrophy in chronic kidney disease, JACC basic to transl Science 7 2022 820 840 10.1016/j.jacbts.2022.03.006
279 Fan Z. Feng Y. Zang L. Guo Y. yi Zhong X. Association of circulating MtDNA with CVD in hemodialysis patients and in vitro effect of exogenous MtDNA on cardiac microvascular inflammation BMC Cardiovasc. Disord. 23 2023 1 10 10.1186/s12872-023-03104-2 36600223
280 Ye W. Tang X. Yang Z. Liu C. Zhang X. Jin J. Lyu J. Plasma-derived exosomes contribute to inflammation via the TLR9-NF-κB pathway in chronic heart failure patients Mol. Immunol. 87 2017 114 121 10.1016/j.molimm.2017.03.011 28433888
281 Prieto-Carrasco R. García-Arroyo F.E. Aparicio-Trejo O.E. Rojas-Morales P. León-Contreras J.C. Hernández-Pando R. Sánchez-Lozada L.G. Tapia E. Pedraza-Chaverri J. Progressive reduction in mitochondrial mass is triggered by alterations in mitochondrial biogenesis and dynamics in chronic kidney disease induced by 5/6 nephrectomy Biology 10 2021 349 10.3390/biology10050349 33919054
282 Kong X. Wang R. Xue Y. Liu X. Zhang H. Chen Y. Fang F. Chang Y. Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression of ROS and mitochondrial biogenesis PLoS One 5 2010 10.1371/journal.pone.0011707
283 Morigi M. Perico L. Rota C. Longaretti L. Conti S. Rottoli D. Novelli R. Remuzzi G. Benigni A. Sirtuin 3–dependent mitochondrial dynamic improvements protect against acute kidney injury J. Clin. Invest. 125 2015 715 726 10.1172/JCI77632 25607838
284 Di W. Lv J. Jiang S. Lu C. Yang Z. Ma Z. Hu W. Yang Y. Xu B. PGC-1: the energetic regulator in cardiac metabolism, Curr Issues Mol. Biol. 28 2018 29 46 10.21775/cimb.028.029
285 Yuan Y. Huang S. Wang W. Wang Y. Zhang P. Zhu C. Ding G. Liu B. Yang T. Zhang A. Activation of peroxisome proliferator-activated receptor-γ coactivator 1α ameliorates mitochondrial dysfunction and protects podocytes from aldosterone-induced injury Kidney Int. 82 2012 771 789 10.1038/ki.2012.188 22648295
286 Zhao W.Y. Zhang L. Sui M.X. Zhu Y.H. Zeng L. Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury Sci. Rep. 6 2016 1 11 10.1038/srep33201 28442746
287 Doi K. Noiri E. Mitochondrial dysfunction in cardiorenal syndrome 10.1089/ars.2016.6654 2016
288 Zhao W. Zhang L. Chen R. Lu H. Sui M. Zhu Y. Zeng L. SIRT3 protects against acute kidney injury via AMPK/mTOR-regulated autophagy Front. Physiol. 9 2018 1 10 10.3389/fphys.2018.01526 29377031
289 Li F. Chen Y. Li Y. Huang M. Zhao W. Geniposide alleviates diabetic nephropathy of mice through AMPK/SIRT1/NF-κB pathway Eur. J. Pharmacol. 886 2020 173449 10.1016/j.ejphar.2020.173449
290 Grynberg K. Ma F.Y. Nikolic-Paterson D.J. The JNK signaling pathway in renal fibrosis Front. Physiol. 8 2017 1 12 10.3389/fphys.2017.00829 28154536
291 Lu L. Lu J. Chen J. Wang B. Peng H. Peng J. Liu X. Lin F. Xiong G. Biomarker identification and pathway analysis of Astragalus membranaceus and Curcuma zedoaria couplet medicines on adenine-induced chronic kidney disease in rats based on metabolomics Front. Pharmacol. 14 2023 1 14 10.3389/fphar.2023.1103527
292 Jiang M. Fan J. Qu X. Li S. Nilsson S.K. Sun Y.B.Y. Chen Y. Yu D. Liu D. Liu B.C. Tang M. Chen W. Ren Y. Nikolic-Paterson D.J. Jiang X. Li J. Yu X. Combined blockade of Smad3 and JNK pathways ameliorates progressive fibrosis in folic acid nephropathy Front. Pharmacol. 10 2019 1 17 10.3389/fphar.2019.00880 30728774
293 Ruiz-Andres O. Suarez-Alvarez B. Sánchez-Ramos C. Monsalve M. Sanchez-Niño M.D. Ruiz-Ortega M. Egido J. Ortiz A. Sanz A.B. The inflammatory cytokine TWEAK decreases PGC-1α expression and mitochondrial function in acute kidney injury Kidney Int. 89 2016 399 410 10.1038/ki.2015.332 26535995
294 Abu Shelbayeh O. Arroum T. Morris S. Busch K.B. PGC-1α is a master regulator of mitochondrial lifecycle and ROS stress response Antioxidants 12 2023 10.3390/antiox12051075
295 Sun J. Leng P. Li X. Guo Q. Zhao J. Liang Y. Zhang X. Yang X. Li J. Salvianolic acid A promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes through regulation of the AMPK-PGC1α signalling pathway Adipocyte 11 2022 562 571 10.1080/21623945.2022.2116790 36053001
296 Wu M. Zhang C. Xie M. Zhen Y. Lai B. Liu J. Qiao L. Liu S. Shi D. Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism Free Radic. Biol. Med. 168 2021 117 128 10.1016/j.freeradbiomed.2021.03.029 33794310
297 Yang X. Liu Q. Li Y. Tang Q. Wu T. Chen L. Pu S. Zhao Y. Zhang G. Huang C. Zhang J. Zhang Z. Huang Y. Zou M. Shi X. Jiang W. Wang R. He J. The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocyte via the AMPK-Sirt1-Pgc-1α signalling pathway Adipocyte 9 2020 484 494 10.1080/21623945.2020.1807850 32835596
298 Marin T.L. Gongol B. Zhang F. Martin M. Johnson D.A. Xiao H. Wang Y. Subramaniam S. Chien S. Shyy J.Y.-J. AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1 Sci. Signal. 10 2017 139 148 10.1126/scisignal.aaf7478
299 Xin Ting Lu Chengzhi SirT3 activates AMPK-related mitochondrial biogenesis and ameliorates sepsis-induced myocardial injury Aging 12 2020 16224 16237 32721927
300 Drake J.C. Wilson R.J. Laker R.C. Guan Y. Spaulding H.R. Nichenko A.S. Shen W. Shang H. Dorn M.V. Huang K. Zhang M. Bandara A.B. Brisendine M.H. Kashatus J.A. Sharma P.R. Young A. Gautam J. Cao R. Wallrabe H. Chang P.A. Wong M. Desjardins E.M. Hawley S.A. Christ G.J. Kashatus D.F. Miller C.L. Wolf M.J. Periasamy A. Steinberg G.R. Hardie D.G. Yan Z. Mitochondria-localized AMPK responds to local energetics and contributes to exercise and energetic stress-induced mitophagy Proc. Natl. Acad. Sci. U.S.A. 118 2021 1 10 10.1073/pnas.2025932118
301 Aquilano K. Vigilanza P. Baldelli S. Pagliei B. Rotilio G. Ciriolo M.R. Peroxisome proliferator-activated receptor γ co-activator 1 α (PGC-1α) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis J. Biol. Chem. 285 2010 21590 21599 10.1074/jbc.M109.070169 20448046
302 Du Y.W. Li X.K. Wang T.T. Zhou L. Li H.R. Feng L. Ma H. Liu H.B. Cyanidin-3-glucoside inhibits ferroptosis in renal tubular cells after ischemia/reperfusion injury via the AMPK pathway Mol. Med. 29 2023 10.1186/s10020-023-00642-5
303 Wei X. Wang Y. Lao Y. Weng J. Deng R. Li S. Lu J. Yang S. Liu X. Effects of honokiol protects against chronic kidney disease via BNIP3/NIX and FUNDC1-mediated mitophagy and AMPK pathways Mol. Biol. Rep. 50 2023 6557 6568 10.1007/s11033-023-08592-1 37338733
304 Moellmann J. Krueger K. Wong D.W.L. Klinkhammer B.M. Buhl E.M. Dehairs J. Swinnen J.V. Noels H. Jankowski J. Lebherz C. Boor P. Marx N. Lehrke M. 2,8-Dihydroxyadenine-induced nephropathy causes hexosylceramide accumulation with increased mTOR signaling, reduced levels of protective SirT3 expression and impaired renal mitochondrial function Biochim. Biophys. Acta, Mol. Basis Dis. 1870 2024 166825 10.1016/j.bbadis.2023.166825
305 Lee H.W. Lee S.M. Lee M.H. Son Y.K. Kim S.E. An W.S. Effect of omega-3 fatty acid on STAMP2 expression in the heart and kidney of 5/6 nephrectomy rat model Mar. Drugs 16 2018 1 11 10.3390/md16110398 29300311
306 Lotfi B. Bagheri Y. Abdollahpour A. Ahmadian E. Matin S. Firouzfar A. Zununi Vahed S. Khajepour F. Protective effect of Eprosartan against ischemic acute renal injury: acting on NF-κB, caspase 3, and Sirtuin 1 Int. Immunopharm. 115 2023 109690 10.1016/j.intimp.2023.109690
307 Li P. Song X. Zhang D. Guo N. Wu C. Chen K. Liu Y. Yuan L. Chen X. Huang X. Resveratrol improves left ventricular remodeling in chronic kidney disease via Sirt1-mediated regulation of FoxO1 activity and MnSOD expression Biofactors 46 2020 168 179 10.1002/biof.1584 31688999
308 Song Z. Xia Y. Shi L. Zha H. Huang J. Xiang X. Li H. Huang H. Yue R. Wang H. Zhu J. Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury Cell. Mol. Biol. Lett. 29 2024 1 23 10.1186/s11658-024-00553-1 38172672
309 Yao M. Liu Y. Sun M. Qin S. Xin W. Guan X. Zhang B. He T. Huang Y. The molecular mechanisms and intervention strategies of mitophagy in cardiorenal syndrome Front. Physiol. 13 2022 1 14 10.3389/fphys.2022.1008517
310 Yang C.-C. Chen Y.-T. Chen C.-H. Li Y.-C. Shao P.-L. Huang T.-H. Chen Y.-L. Sun C.-K. Yip H.-K. The therapeutic impact of entresto on protecting against cardiorenal syndrome-associated renal damage in rats on high protein diet Biomed. Pharmacother. 116 2019 108954 10.1016/j.biopha.2019.108954
311 Tai H. Jiang X.L. Song N. Xiao H.H. Li Y. Cheng M.J. Yin X.M. Chen Y.R. Yang G.L. Jiang X.Y. Kuang J.S. Lan Z.M. Jia L.Q. Tanshinone iia combined with cyclosporine A alleviates lung apoptosis induced by renal ischemia-reperfusion in obese rats Front. Med. 8 2021 1 19 10.3389/fmed.2021.617393
312 Uchida L. Tanaka T. Saito H. Sugahara M. Wakashima T. Fukui K. Nangaku M. Effects of a prolyl hydroxylase inhibitor on kidney and cardiovascular complications in a rat model of chronic kidney disease Am. J. Physiol. Physiol. 318 2020 F388 F401 10.1152/ajprenal.00419.2019
313 Cai C. Wu F. Zhuang B. Ou Q. Peng X. Shi N. Peng L. Li Z. Wang J. Cai S. Tan Y. Empagliflozin activates Wnt/β-catenin to stimulate FUNDC1-dependent mitochondrial quality surveillance against type-3 cardiorenal syndrome Mol. Metabol. 64 2022 101553 10.1016/j.molmet.2022.101553
314 Qi J. Xue Q. Kuang L. Xie L. Luo R. Nie X. Berberine alleviates cisplatin-induced acute kidney injury by regulating mitophagy via PINK 1/Parkin pathway Transl. Androl. Urol. 9 2020 1712 1724 10.21037/tau-20-1129 32944532
315 Liu B. Wang D. Cao Y. Wu J.J. Zhou Y. Wu W. Wu J.J. Zhou J. Qiu J. MitoTEMPO protects against podocyte injury by inhibiting NLRP3 inflammasome via PINK1/Parkin pathway-mediated mitophagy Eur. J. Pharmacol. 929 2022 175136 10.1016/j.ejphar.2022.175136
316 Zhu D. Zhong J. Gong X. Wu X. Augmenter of liver regeneration reduces mitochondria-derived ROS and NLRP3 inflammasome activation through PINK1/Parkin-mediated mitophagy in ischemia-reperfusion-induced renal tubular injury Apoptosis 28 2023 335 347 10.1007/s10495-022-01794-1 36370259
317 Liu N. Ding Y. Zhou H. Chang X. Lou L. Dual-specificity phosphatase 1 interacts with prohibitin 2 to improve mitochondrial quality control against type-3 cardiorenal syndrome Int. J. Med. Sci. 21 2024 547 561 10.7150/ijms.90484 38322592
318 Ishihara M. Urushido M. Hamada K. Matsumoto T. Shimamura Y. Ogata K. Inoue K. Taniguchi Y. Horino T. Fujieda M. Fujimoto S. Terada Y. Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury Am. J. Physiol. Ren. Physiol. 305 2013 495 509 10.1152/ajprenal.00642.2012
319 Yu S.H. Palanisamy K. Sun K.T. Li X. Wang Y.M. Lin F.Y. Chen K.B. Wang I.K. Yu T.M. Li C.Y. Human antigen R regulates hypoxia-induced mitophagy in renal tubular cells through PARKIN/BNIP3L expressions J. Cell Mol. Med. 25 2021 2691 2702 10.1111/jcmm.16301 33496385
320 Zhang W. Guo C. Li Y. Wang H. Wang H. Wang Y. Wu T. Wang H. Cheng G. Man J. Chen S. Fu S. Yang L. Mitophagy mediated by HIF-1α/FUNDC1 signaling in tubular cells protects against renal ischemia/reperfusion injury Ren. Fail. 46 2024 1 13 10.1080/0886022X.2024.2332492
321 Shen Y. Peng X. Ji H. Gong W. Zhu H. Wang J. Dapagliflozin protects heart function against type-4 cardiorenal syndrome through activation of PKM2/PP1/FUNDC1-dependent mitophagy Int. J. Biol. Macromol. 250 2023 126116 10.1016/j.ijbiomac.2023.126116
322 Li Q. Liao J. Chen W. Zhang K. Li H. Ma F. Zhang H. Han Q. Guo J. Li Y. Hu L. Pan J. Tang Z. NAC alleviative ferroptosis in diabetic nephropathy via maintaining mitochondrial redox homeostasis through activating SIRT3-SOD2/Gpx4 pathway Free Radic. Biol. Med. 187 2022 158 170 10.1016/j.freeradbiomed.2022.05.024 35660452
323 Peerapanyasut W. Kobroob A. Palee S. Chattipakorn N. Wongmekiat O. Activation of sirtuin 3 and maintenance of mitochondrial integrity by N-acetylcysteine protects against bisphenol A-induced kidney and liver toxicity in rats Int. J. Mol. Sci. 20 2019 10.3390/ijms20020267
324 Sharma M. Kaur T. Singla S.K. Protective effects of N-acetylcysteine against hyperoxaluria induced mitochondrial dysfunction in male wistar rats Mol. Cell. Biochem. 405 2015 105 114 10.1007/s11010-015-2402-6 25842190
325 Nam B.Y. Jhee J.H. Park J.T.J. Kim S. Kim G. Park J.T.J. Yoo T.H. Kang S.W. Yu J.W. Han S.H. PGC-1α inhibits the NLRP3 inflammasome via preserving mitochondrial viability to protect kidney fibrosis Cell Death Dis. 13 2022 1 12 10.1038/s41419-021-04480-3
326 Gao Q. Zhu H. The overexpression of sirtuin1 (SIRT1) alleviated lipopolysaccharide (LPS)-induced acute kidney injury (AKI) via inhibiting the activation of nucleotide-binding oligomerization domain-like receptors (NLR) family Pyrin domain containing 3 (NLRP3) Inflammas Med. Sci. Mon. Int. Med. J. Exp. Clin. Res. 25 2019 2718 2726 10.12659/MSM.913146
327 Peerapanyasut W. Kobroob A. Palee S. Chattipakorn N. N-acetylcysteine attenuates the increasing severity of distant organ liver dysfunction after acute kidney injury in rats exposed to bisphenol A Antioxidants 8 2019 497 10.3390/antiox8100497 31640182
328 Lambona C. Zwergel C. Valente S. Mai A. SIRT3 activation a promise in drug development? New insights into SIRT3 Biology and its implications on the drug discovery process J. Med. Chem. 67 2024 1662 1689 10.1021/acs.jmedchem.3c01979 38261767
329 Azminah A. Erlina L. Radji M. Mun A. Riadhi R. In silico and in vitro identi fi cation of candidate SIRT1 activators from Indonesian medicinal plants compounds database Comput. Biol. Chem. 83 2019 107096 10.1016/j.compbiolchem.2019.107096
330 Guan X. Upadhyay A. Krishna R. Munshi S. Roy S. Computationally driven discovery and characterization of SIRT3 activating compounds that fully recover catalytic activity under NAD + depletion bioRxiv 2023
331 Dai H. Case A.W. V Riera T. Considine T. Lee J.E. Hamuro Y. Zhao H. Jiang Y. Sweitzer S.M. Pietrak B. Schwartz B. Blum C.A. Disch J.S. Caldwell R. Szczepankiewicz B. Oalmann C. Ng P.Y. White B.H. Casaubon R. Narayan R. Koppetsch K. Bourbonais F. Wu B. Wang J. Qian D. Jiang F. Mao C. Wang M. Hu E. Wu J.C. Perni R.B. Vlasuk G.P. Ellis J.L. Crystallographic structure of a small molecule SIRT1 activator-enzyme complex Nat. Commun. 6 2015 1 10 10.1038/ncomms8645
332 Alqarni M.H. Foudah A.I. Muharram M.M. Labrou N.E. The pleiotropic function of human sirtuins as modulators of metabolic pathways and viral infections Cells 10 2021 1 20 10.3390/cells10020460
333 Cao D. Wang M. Qiu X. Liu D. Jiang H. Yang N. Xu R.M. Structural basis for allosteric, substratedependent stimulation of SIRT1 activity by resveratrol Genes Dev. 29 2015 1316 1325 10.1101/gad.265462.115 26109052
334 Liu J. Zhang T. Zhu J. Ruan S. Li R. Guo B. Honokiol attenuates lipotoxicity in hepatocytes via activating SIRT3 - AMPK mediated lipophagy Chin. Med. 2021 1 13 10.1186/s13020-021-00528-w 33407732
335 Reverdy C. Gitton G. Guan X. Adhya I. Krishna Dumpati R. Roy S. Chall S. Ghosh A. Errasti G. Delacroix T. Chakrabarti R. Discovery of novel compounds as potent activators of Sirt3 Bioorg. Med. Chem. 73 2022 10.1016/j.bmc.2022.116999
336 Morris A.J. M G. Huey R. Lindstrom W. Sanner M.F. Belew R.K. Goodsell D.S. Olson AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility J. Comput. Chem. 30 2009 2785 2791 19399780
337 Pettersen E.F. Goddard T.D. Huang C.C. Couch G.S. Greenblatt D.M. Meng E.C. Ferrin T.E. UCSF Chimera - a visualization system for exploratory research and analysis J. Comput. Chem. 25 2004 1605 1612 10.1002/jcc.20084 15264254
338 Wang Y. Lu M. Xiong L. Fan J. Zhou Y. Li H. Peng X. Zhong Z. Wang Y. Huang F. Chen W. Yu X. Mao H. Drp1-mediated mitochondrial fission promotes renal fibroblast activation and fibrogenesis Cell Death Dis. 11 2020 10.1038/s41419-019-2218-5
339 Tang C. Han H. Yan M. Zhu S. Liu J. Liu Z. He L. Tan J. Liu Y. Liu H. Sun L. Duan S. Peng Y. Liu F. Yin X.M. Zhang Z. Dong Z. PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury Autophagy 14 2018 880 897 10.1080/15548627.2017.1405880 29172924
340 Li S. Lin Q. Shao X. Zhu X. Wu J. Wu B. Zhang M. Zhou W. Zhou Y. Jin H. Zhang Z. Qi C. Shen J. Mou S. Gu L. Ni Z. Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction Free Radic. Biol. Med. 152 2020 632 649 10.1016/j.freeradbiomed.2019.12.005 31825802
341 Wu Y. Jiang T. Hua J. Xiong Z. Dai K. Chen H. Li L. Peng J. Peng X. Zheng Z. Xiong W. PINK1/Parkin-mediated mitophagy in cardiovascular disease: from pathogenesis to novel therapy Int. J. Cardiol. 361 2022 61 69 10.1016/j.ijcard.2022.05.025 35594994
342 Shi S. Zhang B. Li Y. Xu X. Lv J. Jia Q. Chai R. Xue W. Li Y. Wang Y. Wu H. Song Q. Hu Y. Mitochondrial dysfunction: an emerging link in the pathophysiology of cardiorenal syndrome Front. Cardiovasc. Med. 9 2022 1 16 10.3389/fcvm.2022.837270
343 Kwiatkowska E. Kwiatkowski S. Dziedziejko V. Tomasiewicz I. Domański L. Renal microcirculation injury as the main cause of ischemic acute kidney injury development Biology 12 2023 10.3390/biology12020327
344 Huette P. Moussa M.D. Beyls C. Guinot P.G. Guilbart M. Besserve P. Bouhlal M. Mounjid S. Dupont H. Mahjoub Y. Michaud A. Abou-Arab O. Association between acute kidney injury and norepinephrine use following cardiac surgery: a retrospective propensity score-weighted analysis Ann. Intensive Care 12 2022 1 9 10.1186/s13613-022-01037-1 34981245
345 Charytan D.M. Soomro Q.H. Caporotondi A. Guazzotti G. Maestri R. Pinna G.D. La Rovere M.T. Baroreceptor sensitivity in individuals with CKD and heart failure Kidney 3 2022 2027 2035 10.34067/KID.0004812022
346 Scalise F. Quarti-Trevano F. Toscano E. Sorropago A. Vanoli J. Grassi G. Renal denervation in end-stage renal disease: current evidence and perspectives, high blood press Cardiovasc. Prev. 31 2024 7 13 10.1007/s40292-023-00621-1
347 Hayashi K. Shimokawa T. Yamagata M. Yoneda K. Inhibition of α2-adrenoceptor is renoprotective in 5/6 nephrectomy-induced chronic kidney injury rats J. Pharmacol. Sci. 145 2021 79 87 10.1016/j.jphs.2020.11.001 33357783
348 Tsutsui H. Tanaka R. Yamagata M. Yukimura T. Ohkita M. Matsumura Y. Protective effect of ischemic preconditioning on ischemia/reperfusion- induced acute kidney injury through sympathetic nervous system in rats Eur. J. Pharmacol. 718 2013 206 212 10.1016/j.ejphar.2013.08.032 24036256
349 Mutoh J. Ohsawa M. Hisa H. Involvement of renal sympathetic nerve activation on the progression of ischemic acute kidney injury in the mouse J. Pharmacol. Sci. 125 2014 415 421 10.1254/jphs.13234FP 25069611
350 xia Xu H. mei Cui S. mei Zhang Y. Ren J. Mitochondrial Ca2+ regulation in the etiology of heart failure: physiological and pathophysiological implications Acta Pharmacol. Sin. 41 2020 1301 1309 10.1038/s41401-020-0476-5 32694759
351 Nehme A. Zouein F.A. Zayeri Z.D. Zibara K. An update on the tissue renin angiotensin system and its role in physiology and pathology J. Cardiovasc. Dev. Dis. 6 2019 1 17 10.3390/jcdd6020014
352 Watanabe H. Belyea B.C. Paxton R.L. Li M. Dzamba B.J. DeSimone D.W. Gomez R.A. Sequeira-Lopez M.L.S. Renin cell baroreceptor, a nuclear mechanotransducer central for homeostasis Circ. Res. 129 2021 262 276 10.1161/CIRCRESAHA.120.318711 33993729
353 Maryam T.P. Varghese T.B. Unraveling the complex pathophysiology of heart failure: insights into the role of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) Curr. Probl. Cardiol. 49 2024 10.1016/j.cpcardiol.2024.102411
354 Ke H.Y. Chin L.H. Tsai C.S. Lin F.Z. Chen Y.H.Y.C. Chang Y.L. Huang S.M. Chen Y.H.Y.C. Lin C.Y. Cardiac calcium dysregulation in mice with chronic kidney disease J. Cell Mol. Med. 24 2020 3669 3677 10.1111/jcmm.15066 32064746
355 Junho C.V.C. González-Lafuente L. Navarro-García J.A. Rodríguez-Sánchez E. Carneiro-Ramos M.S. Ruiz-Hurtado G. Unilateral acute renal ischemia-reperfusion injury induces cardiac dysfunction through intracellular calcium mishandling Int. J. Mol. Sci. 23 2022 10.3390/ijms23042266
356 Gul R. Dar M.A. Nawaz S. Alfadda A.A. Protective effects of nanoceria against mitochondrial dysfunction and angiotensin II-induced hypertrophy in H9c2 cardiomyoblasts Antioxidants 12 2023 10.3390/antiox12040877
357 Ravarotto V. Bertoldi G. Innico G. Gobbi L. Calò L.A. The pivotal role of oxidative stress in the pathophysiology of cardiovascular-renal remodeling in kidney disease Antioxidants 10 2021 10.3390/antiox10071041
358 Govender J. Loos B. Marais E. Engelbrecht A.M. Melatonin improves cardiac and mitochondrial function during doxorubicin-induced cardiotoxicity: a possible role for peroxisome proliferator-activated receptor gamma coactivator 1-alpha and sirtuin activity? Toxicol. Appl. Pharmacol. 358 2018 86 101 10.1016/j.taap.2018.06.031 29966675
359 Ishigaki S. Ohashi N. Matsuyama T. Isobe S. Tsuji N. Iwakura T. Fujikura T. Tsuji T. Kato A. Miyajima H. Yasuda H. Melatonin ameliorates intrarenal renin–angiotensin system in a 5/6 nephrectomy rat model Clin. Exp. Nephrol. 22 2018 539 549 10.1007/s10157-017-1505-7 29159527
360 Rosner M.H. Reis T. Husain-Syed F. Vanholder R. Hutchison C. Stenvinkel P. Blankestijn P.J. Cozzolino M. Juillard L. Kashani K. Kaushik M. Kawanishi H. Massy Z. Sirich T.L. Zuo L. Ronco C. Classification of uremic toxins and their role in kidney failure, clin J. Am. Soc. Nephrol. 16 2021 1918 1928 10.2215/CJN.02660221
361 Fernandes S.R. Meireles A.N. Marques S.S. Silva L. Barreiros L. Sampaio-Maia B. Miró M. Segundo M.A. Sample preparation and chromatographic methods for the determination of protein-bound uremic retention solutes in human biological samples: an overview J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 1215 2023 10.1016/j.jchromb.2022.123578
362 Popkov V.A. Silachev D.N. Zalevsky A.O. Zorov D.B. Plotnikov E.Y. Mitochondria as a source and a target for uremic toxins Int. J. Mol. Sci. 20 2019 10.3390/ijms20123094
363 Zwaenepoel B. De Backer T. Glorieux G. Verbeke F. Predictive value of protein-bound uremic toxins for heart failure in patients with chronic kidney disease, ESC Hear Fail. 11 2024 466 474 10.1002/ehf2.14566
364 Caillard P. Bennis Y. Six I. Bodeau S. Kamel S. Choukroun G. Maizel J. Titeca-Beauport D. The role of gut-derived, protein-bound uremic toxins in the cardiovascular complications of acute kidney injury Toxins 14 2022 1 14 10.3390/toxins14050336
365 Enoki Y. Watanabe H. Arake R. Fujimura R. Ishiodori K. Imafuku T. Nishida K. Sugimoto R. Nagao S. Miyamura S. Ishima Y. Tanaka M. Matsushita K. Komaba H. Fukagawa M. Otagiri M. Maruyama T. Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction J. Cachexia. Sarcopenia Muscle. 8 2017 735 747 10.1002/jcsm.12202 28608457
366 Sun C.Y. Cheng M.L. Pan H.C. Lee J.H. Lee C.C. Protein-bound uremic toxins impaired mitochondrial dynamics and functions Oncotarget 8 2017 77722 77733 10.18632/oncotarget.20773 29100420
367 Tan X. Sen Cao X. Zhang P. Xiang F.F. Teng J. Zou J.Z. Ding X.Q. Endoplasmic reticulum stress associated apoptosis as a novel mechanism in indoxyl sulfate-induced cardiomyocyte toxicity Mol. Med. Rep. 18 2018 5117 5122 10.3892/mmr.2018.9496 30272270
368 Shen W.C. Chou Y.H. Shi L.S. Chen Z.W. Tu H.J. Lin X.Y. Wang G.J. Ast-120 improves cardiac dysfunction in acute kidney injury mice via suppression of apoptosis and proinflammatory nf-κb/icam-1 signaling J. Inflamm. Res. 14 2021 505 518 10.2147/JIR.S283378 33658826
369 Shen W.C. Chou Y.H. Huang H.P. Sheen J.F. Hung S.C. Chen H.F. Induced pluripotent stem cell-derived endothelial progenitor cells attenuate ischemic acute kidney injury and cardiac dysfunction Stem Cell Res. Ther. 9 2018 1 12 10.1186/s13287-018-1092-x 29291747
370 Yang K. Wang C. Nie L. Zhao X. Gu J. Guan X. Wang S. Xiao T. Xu X. He T. Xia X. Wang J. Zhao J. Klotho protects against indoxyl sulphate-induced myocardial hypertrophy J. Am. Soc. Nephrol. 26 2015 2434 2446 10.1681/ASN.2014060543 25804281
371 Koizumi M. Tatebe J. Watanabe I. Yamazaki U. Ikeda T. Morita T. Aryl hydrocarbon receptor mediates indoxyl sulfate-induced cellular senescence in human umbilical vein endothelial cells J. Atherosclerosis Thromb. 21 2014 904 916 10.5551/jat.23663
372 Nakagawa K. Itoya M. Takemoto N. Matsuura Y. Tawa M. Matsumura Y. Ohkita M. Indoxyl sulfate induces ROS production via the aryl hydrocarbon receptor-NADPH oxidase pathway and inactivates NO in vascular tissues Life Sci. 265 2021 118807 10.1016/j.lfs.2020.118807
373 Capomolla S. Opasich C. Riccardi G. Febo O. Riccardi R. Cobelli F. Tavazzi L. Beta blockade therapy in chronic heart failure: diastolic function and mitral regurgitation improvement by carvedilol J. Am. Coll. Cardiol. 31 1998 189 10.1016/S0735-1097(98)81462-9
374 Lou W. di Zhang M. Chen Q. Bai T.Y. Hu Y.X. Gao F. Li J. Lv X.L. Zhang Q. Chang F.H. Molecular mechanism of benzo [a] pyrene regulating lipid metabolism via aryl hydrocarbon receptor Lipids Health Dis. 21 2022 1 12 10.1186/s12944-022-01627-9 34991597
375 Dou L. Sallée M. Cerini C. Poitevin S. Gondouin B. Jourde-Chiche N. Fallague K. Brunet P. Calaf R. Dussol B. Mallet B. Dignat-George F. Burtey S. The cardiovascular effect of the uremic solute indole-3 acetic acid J. Am. Soc. Nephrol. 26 2015 876 887 10.1681/ASN.2013121283 25145928
376 Juni R.P. Al-Shama R. Kuster D.W.D. van der Velden J. Hamer H.M. Vervloet M.G. Eringa E.C. Koolwijk P. van Hinsbergh V.W.M. Empagliflozin restores chronic kidney disease–induced impairment of endothelial regulation of cardiomyocyte relaxation and contraction Kidney Int. 99 2021 1088 1101 10.1016/j.kint.2020.12.013 33359500
377 Han H. Zhu J. Zhu Z. Ni J. Du R. Dai Y. Chen Y. Wu Z. Lu L. Zhang R. P-cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes J. Am. Heart Assoc. 4 2015 1 11 10.1161/JAHA.115.001852
