
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

39252224
MD-D-24-02731
00011
10.1097/MD.0000000000039567
3
5200
Research Article
Systematic Review and Meta-Analysis
Spotlight on endoplasmic reticulum stress in acute kidney injury: A bibliometric analysis and visualization from 1997 to 2024
Yang Yuan MD 20223916@stu.hnucm.edu.cn
abcd
Yuan Fang MD fang-yuan@cssdsyy.com
bcd
Xiang Debiao PhD Debiao-xiang@cssdsyy.com
bcd
Wang Pengkai MD wangpengkai199903@163.com
abcd
Yang Rui MD yangrui20210228@163.com
abcd
https://orcid.org/0000-0002-8866-6848
Li Xin PhD bcd*
a Hunan University of Chinese Medicine, Changsha, Hunan, China
b Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan, China
c Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs, Changsha, Hunan, China
d Institute of Clinical Application of Antibiotics, Changsha, Hunan, China.
* Correspondence: Xin Li, Department of Pharmacy, The Third Hospital of Changsha, Changsha, Hunan 410015, China (e-mail: xin-li@cssdsyy.com).
06 9 2024
06 9 2024
103 36 e3956714 3 2024
13 8 2024
14 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Background:

Endoplasmic reticulum (ER) stress, a protective stress response of body and play important role in maintain ER stability. Acute kidney injury (AKI) is a severe syndrome, and the molecular mechanisms of AKI has not been fully elucidated. With an increasing understanding of ER stress, ER stress has been investigated and considered a potential and novel therapeutic target in AKI. This study aims to employ a bibliometric approach to analyze research trends and focal points in ER stress associated with AKI over 3 decades.

Methods:

Data were retrieved from the Web of Science Core Collection on April 15, 2024. CiteSpace and VOSviewer bibliometric software were mainly used to measure bibliometrics and analyze knowledge graphs to predict the latest research trends in the field.

Results:

There were 452 “ER stress in AKI” articles in the Web of Science Core Collection. According to the report, China and the United States were the leading research drivers in this field. Central South University was the most active academic institution, contributing the most documents. In this field, Dong Zheng was the most prolific author. The American Journal of Physiology-Renal Physiology was the journal with the most records among all journals. The keywords “NLRP3 inflammasome,” “redox signaling,” and novel forms of cell death such as “ferroptosis” may represent current research trends and directions.

Conclusion:

The bibliometric analysis comprehensively examines the trends and hotspots on “ER stress and AKI.” Studies on AKI related to stress in the ER are still in their infancy. Research should focus on understanding the relationship between ER stress and inflammasome, redox signal pathways and new forms of cell death such as ferroptosis.

acute kidney injury
bibliometric analysis
endoplasmic reticulum stress
visualization
Web of Science
the Hunan Provincial Key Laboratory of Anti-Resistance Microbial DrugsNo:2023TP1013 Yuan Yangthe Changsha Science and Technology ProjectNo: kq2208464 Yuan Yangthe Changsha Science and Technology ProjectNO:kq2208463 Yuan YangOPEN-ACCESSTRUE
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pmc1. Introduction

Acute kidney injury (AKI), a global public health problem, has high morbidity and mortality worldwide, specifically in developing countries.[1] Clinically, it is characterized by increased serum creatinine and an acute reduction in the glomerular filtration rate.[2,3] Still now, the pathogenesis of AKI is not well defined, and there are no satisfactory pharmacologic interventions or surgical options to prevent or treat AKI.[4] Learning more about the pathogenesis of AKI and identify new therapeutic targets is urgent.

The endoplasmic reticulum (ER) is a eukaryotic organelle responsible for protein folding, maturation, lipid synthesis, calcium homeostasis, and secretory proteins. Correctly folded and assembled proteins exit the ER and can be transported to the Golgi apparatus and other cellular destinations, whereas unfolded and misfolded proteins are retained in the ER. Their accumulation induces ER stress.[5] A specific signaling pathway, the unfolded protein response (UPR), is activated to relieve ER stress and restore cell homeostasis.[6–8] UPR is composed of 3 distinct ER signaling pathways, which have 3 key stress sensors: inositol-requiring enzyme-1 (IRE1), protein kinase RNA PKR-like ER-resident kinase (PERK), and activating transcription factor 6 (ATF6).[9] In the absence of stress, the UPR signaling pathways are inactive. Under ER stress, the initial UPR is a pro-survival mechanism to restore intracellular homeostasis and cell viability. However, when ER stress is severe and insurmountable, UPR activation triggers pro-death mechanisms and induces cell death.[10]

Recent studies reveal that ER homeostasis is crucial and possess vital role in virous disease including neurodegenerative diseases, liver disease, diabetes, and cardiovascular diseases. In kidney, ER stress was also investigated and shown to be involved in the progression of AKI.[11] A study in 2007 has shown that ER stress inducers alleviated drugs-induced cytotoxicity in kidney cells and ameliorated ischemic AKI in vivo.[12] Also, overexpression of ER chaperone proteins (such as ORP150) has been shown to demonstrate renoprotective effects in ischemic AKI.[13] Another study in 2012 has indicated that the inhibition of severe ER stress using tauroursodeoxycholic acid (TUDCA, a bile acid derivative with chaperone properties) could improve renal tubule damage in ischemic AKI.[14] Above research has implicated that ER stress and UPR pathway play an important bidirectional role in AKI. According literature, we acknowledged that UPR factors including GRP78, CHOP, PERK, eIF2α, ATF4, ATF6, XBP1, IRE1α, eIF2α participated in ER stress induced AKI.[15–25]

Bibliometric analysis is a tool that provides information to determine the evolving trends and the focus of research topics in various fields.[26] This study used bibliometric analysis to identify research growth, countries, authors, journals, citations, keywords, and collaborations on “ER stress in AKI” and offer a new perspective for the elucidation of underlying pathological mechanism of AKI, as well as potential biological targets.

2. Methods

2.1. Data retrieval and collection

The Science Citation Index-expanded from the WOS (Web of Science) Core Collection provides comprehensive data and is the most authoritative, frequently used, and appropriate database for bibliometric analysis.[27] All data in this study were derived from the WOS database. The study data were retrieved on April 15, 2024. The search of the database is as follows: “(TS = (‘acute kidney injury’) OR TS = (‘acute renal failure’) OR TS = (‘acute renal injury’) OR TS = (‘acute kidney failure’) OR TS = (‘acute renal impairment’)) AND (TS = (endoplasmic reticulum stress)) AND (DT = (Article) OR DT = (Review))) AND LA = (English).” We collected data and downloaded the “Full record and cited references” of the literature in “plain text” format in the Science Citation Index-expanded of the WOS Core Collection. Furthermore, data were collected only for the type of review articles and articles, with language restricted to English.

2.2. Data analysis and visualization

Visualization software determines information related to the literature according to the information of the first author in the article, including countries (regions), authors, journals, keywords, and research institutions.[28] We mainly used Citespace and VOSviewer software to process, analyze, and visualize the dataset and co-occurrence. In addition, the chord diagram was produced using the online platform (http://www.highcharts.com) and the map was prepared using ArcMap software.

3. Results

3.1. Trend of publications and citations

From 1997 to 2024, 452 articles from the WOS Core Collection were included: 307 articles and 145 review articles. These articles were from 48 countries/regions, 2634 authors, 226 journals, and 17,262 co-cited references. Furthermore, the citation analysis indicated that these articles received 21,128 citations, with an average of 46.74 per document and an H-index of 64. The past 3 decades have witnessed a remarkable growth in research interest in studying AKI-related ER stress (Fig. 1).

Figure 1. The annual number and cumulative publications related to this topic.

3.2. Countries/regions and organizations analysis

From 1997 to 2024, 48 countries/regions contributed to the publication of studies in the field of ER stress related to AKI, with China (238) and the United States (119) contributing the most (Fig. 2A and Table 1). The rest of the countries/regions published fewer articles. Although China published the most articles, accounting for 52.65% of all articles, it was behind in collaborations with other countries (Fig. 2B). In contrast, the United States cooperated closely with other countries and had the highest citations and average citations per article (Table 1). In bibliometric analysis, the main index for evaluating the quality of an article was the number of citations it received.[29] Therefore, Chinese scholars should focus on improving the level of articles to enhance to improve human knowledge in general.

Table 1 Top 10 productive countries/regions related to ER stress in AKI.

Rank	Countries/regions	Documents (N)	Percentage (N/452)	Citations	
1	China	238	52.65	7785	
2	The United States	119	26.32	11,871	
3	France	23	5.08	780	
4	Japan	21	4.64	1024	
5	South Korea	17	3.76	420	
6	Germany	15	3.32	1024	
7	England	11	2.79	195	
8	Spain	11	2.43	1293	
9	Mexico	10	2.21	162	
10	Canada	9	1.99	600	
AKI = acute kidney injury, ER = endoplasmic reticulum.

Figure 2. (A) An overview of the number of articles published by country in the world. (B) Academic cooperation between countries/regions on this topic.

The articles retrieved were published by 645 different organizations. In Table 2, the top 3 organizations by number of articles were China (7/10), the United States (2/10), and France (1/10). Total link strength (TLS) represents the total number of co-occurrences positively correlated with the strength of cooperation.[30] Central South University and Charlie Norwood VA Medical Center had the highest TLS, indicating that they actively participated in the most collaborations with other organizations worldwide. Regarding citations, Central South University ranked first, followed by Wuhan University.

Table 2 Top 10 institutions ranked by the numbers of publications.

Rank	Institutions	Documents (N)	Citations	TLS	Countries/regions	
1	Central South University	24	3163	16	China	
2	Wuhan University	14	509	9	China	
3	Charlie Norwood VA Medical Center	12	2537	17	United States	
4	Capital Medical University	12	145	2	China	
5	Sichuan University	12	188	0	China	
6	Augusta University	10	443	14	United States	
7	University of Paris Descartes (Paris 5)	10	469	11	France	
8	Shanghai Jiao Tong University	10	100	2	China	
9	National Taiwan University	9	324	4	China	
10	Qingdao University	9	207	3	China	

3.3. Citation authors

A total of 2634 authors participated in the AKI-related ER stress study. The top 10 highly productive authors are listed in Table 3. Dong Zheng (15), Pallet Nicolas (12), and Ma Liang (11) were the top 3. The author Dong Zheng became the leading figure with the highest total citation frequencies (1305). The co-occurrence analysis of the authors is beneficial in analyzing the document’s distribution and identifying the strength of collaboration between the core authors and the authors.[31] In Figure 3, created by CiteSpace, each node represents one author, the number of articles published by the author determines the size of each node and the font, and the connecting lines between the nodes represent the existence of cooperative relationships between the authors. We can see that the core authors and the team worked closely together, such as Ma, Liang, Fu, Ping, Guo, Fan, Liang, Yan. However, there was a general lack of cooperation between the various groups.

Table 3 Top 10 authors in the field of ER stress in AKI.

Rank	Author	Documents (N)	Citations	
1	Dong, Zheng	15	1305	
2	Pallet, Nicolas	12	395	
3	Ma, Liang	11	173	
4	Fu, Ping	9	157	
5	Guo, Fan	9	157	
6	Liu, Jing	8	175	
7	Li, Lingzhi	7	121	
8	Liang, Yan	7	103	
9	Huang, Rongshuang	6	88	
10	Lee, Moon-Seung	6	133	
AKI = acute kidney injury, ER = endoplasmic reticulum.

Figure 3. The author cooperation map.

3.4. Journal analysis

All articles on the topic were published in 226 different journals. Five journals published 10 to 20 documents, 12 published 5 to 10 documents, and the rest of the journals published 1 to 4 articles each. In Table 4, the journal with the most publications were the American Journal of Physiology Renal Physiology, with 20 articles. The Journal Citation Reports for 2023 indicates that 8 of the top 10 academic journals are in Q1. There were 2 journals with impact factors >10, and Kidney International earned the highest impact factors (19.60).

Table 4 Top 10 journals associated to the research on ER stress in AKI.

Rank	Journal title	Documents (N)	Citations	IF	JCR	Country	
1	American Journal of Physiology Renal Physiology	20	927	4.2	Q1	United States	
2	Frontiers in Pharmacology	15	207	5.6	Q1	Switzerland	
3	International Journal of Molecular Sciences	13	304	5.6	Q1	United States	
4	Kidney International	13	2944	19.6	Q1	United States	
5	PLOS One	11	407	3.7	Q2	United States	
6	Biomedicine Pharmacotherapy	8	152	7.5	Q1	France	
7	Cell Death and Disease	8	193	9	Q1	England	
8	Journal of The American Society of Nephrology	8	722	13.6	Q1	United States	
9	Life Sciences	7	162	6.1	Q1	England	
10	Oxidative Medicine and Cellular Longevity	7	262	7.31	Q2	United States	
AKI = acute kidney injury, ER = endoplasmic reticulum.

Dual-map overlay analysis of journals is a novel method to display the distribution of the studies of each subject, the citation trajectories, and the information flow.[32] In Figure 4, on the left are the cited journals, and on the right are the co-cited journals. The former represents the cutting edge of research, whereas the latter represents the foundation of studies. Most publications have been published in molecular, biology, and immunology journals. In addition, most publications were cited in medicine, biology, genetics, health, and nursing journals.

Figure 4. Dual-map overlap of journals on ER stress in AKI research. AKI = acute kidney injury, ER = endoplasmic reticulum.

3.5. Analysis of co-cited references

The co-cited references were cited by other publications.[33] The 17,262 co-cited references were included in the 452 retrieved articles. The title of the text “Ferroptosis: process and function” by Xie Y had the highest number of co-citations in Table 5 (n = 1691). “Cisplatin nephrotoxicity: Mechanisms and reno-protective strategies” by Pabla N and Dong Z occupied the second place with 1332 citations. A co-citation network, based on cited references, can provide wider and deeper knowledge related to the research domain. The cited references are representing in the form of nodes and the co-citation relationships are visualized in the form of links (Fig. 5A). Figure 5B shows the co-citation network created by CiteSpace, which contains ten clusters by keywords that served as label sources. The cluster analysis revealed that the top 3 clusters ranked by cluster size[34] were “osmotic stress,” “unfolded protein response,” and “ferroptosis.”

Table 5 The top 10 co-cited references involved in ER stress in AKI.

Rank	Title	First author	Journal	Citations	
1	Ferroptosis: process and function	Xie, Y	Cell Death and Differentiation	1691	
2	Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies	Pabla, N and Dong, Z	Kidney International	1332	
3	Acute Kidney Injury	Zuk, A and Bonventre, JV	Annual Review of Medicine	444	
4	New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view	Lopez Novoa	Kidney International	438	
5	Cisplatin nephrotoxicity: a review of the literature	Manohar, S and Leung, N	Journal of Nephrology	370	
6	Mediators of Inflammation in Acute Kidney Injury	Akcay, A	Mediators of Inflammation	355	
7	Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases	Cybulsky, AV	Nature Reviews Nephrology	288	
8	Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update	Dos, Santos	Actives of Toxicology	264	
9	Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology	Zhan, M	Kidney international	252	
10	Autophagy in acute kidney injury	Kaushal, GP	Kidney international	252	
AKI = acute kidney injury, ER = endoplasmic reticulum.

Figure 5. (A) Co-citation analysis of references. (B) Cluster diagram of co-cited references using keywords as label source.

3.6. Analysis of keywords

In Figure 6A, VOSviewer revealed 2 main keyword clusters. The size of the nodes reflects the frequency of occurrence of the keywords, while the distance between 2 points reflects the strength of the association. Keywords with a closer distance were classified into the same cluster, which roughly reflects the main topics in the ER stress in AKI research area. The red cluster contained “unfolded protein response,” “reactive oxygen species,” “apoptosis,” “inflammation.” The green cluster is mainly composed of “acute kidney injury,” “endoplasmic reticulum stress,” “autophagy” and “oxidative stress.” VOSviewer marked the keywords with different colors on the visualization map, which varies according to the average publication year. The keywords that appeared earlier are colored in purple, while the yellow color represents the keywords that have appeared recently. In Figure 6B, “NLRP3 inflammasome,” “redox signaling,” “ferroptosis,” “pyroptosis,” “necroptosis,” and “mitochondrial dysfunction” provided a current focus of research.

Figure 6. (A) The author keywords co-occurrence network map, which showed the distribution of clusters of major keywords. (B) The overlay visualization map showed the color change of the author keywords based on average occurrence time.

4. Discussion

Based on bibliometric analysis, we present a comprehensive overview of the development of AKI-related ER stress and suggest future research directions. The number of publications has increased year after year, indicating that ER stress in AKI will remain a hot research topic. China and the United States lead the world in research on this topic. This conclusion is consistent with the fact that 7 of the top 10 organizations in publications were published in China. Upon author analysis, Dong Zheng is the leading author, and has the most significant number of citations and publications. The top ten journals collectively produce approximately one-third of the articles. In this study, a trend of multidisciplinary development is also evident, as the top 10 journals include journals from nephrology and other fields.

The study “Ferroptosis: process and function” by Xie Y et al is recognized as the most frequently referenced research in the field. The article refers to the up-regulation of ER stress involved in ferroptosis induction. Several ER stress markers, such as eIF2α and ATF4 protein, were observed to increase levels after treatment with ferroptosis inducers.[35] The heading “Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies” by Pabla N and Dong Z holds the second highest citation times. It is essential to note that the ER stress pathway contributes to renal tubular cell apoptosis.[36] A third study, “Acute Kidney Injury,” is a review written by Zuk A. and Bonventre JV, focusing primarily on the intersection between ER stress, mitochondrial dysfunction, autophagy, inflammatory response, and cell death.[37]

According to the bibliometric analysis in the study, we confirmed ER stress plays an important role in AKI. Activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, redox signaling and ferroptosis in ER stress-mediated AKI become a focus of research. Thus, we furtherly analyzed the relationships between NLRP3 inflammasome, redox signaling and ER stress in AKI from the citation burst, and the visualization of keywords overlay.

Firstly, ER stress mediates inflammation activation, which accelerated the progress of AKI (Fig. 7A).[38] The NLRP3 inflammasome is a protein complex consisting of the intracellular innate immune receptor NLRP3, the adapter protein apoptosis-associated speck-containing protein with a CARD, and the protease caspase-1.[39] An experimental study demonstrated that ER stress-mediated NLRP3 inflammasome activation may represent a new mechanism for the renal rennin-angiotensin system to induce tubulointerstitial inflammation in renal injury.[40] Furthermore, another study highlighted the renoprotective effects of an essential polyphenolic constituent and its mechanisms are mainly associated with the repression of ER stress-mediated NLRP3 inflammasome overactivation.[41] ER stress can activate the NLRP3 inflammasome through the 3 branches of the UPR.[42,43] Specifically, ER stress through the PERK and IRE1 pathways of UPR induces TXNIP expression, which induces the activation of the NLRP3 inflammasome.[44] Unlike the pathways of IRE1 and PERK, the ATF6 pathway can cause NF-κB activation, inducing the expression of pro-IL-1β and NLRP3.[45,46] In a murine model of cisplatin-induced AKI, Alleviated ER stress and NF-κB signaling could suppress the expression of NLRP3 inflammasome, and improve tubular injury.[47] The NLRP3 inflammasome activated by the UPR pathways recruits and activates pro-inflammatory caspase-1, which cleaves interleukin 1β and interleukin 18 precursors in their mature forms to mediate various inflammatory diseases.[48] Activation of the NLRP3 inflammasome participates in the progression of nephropathy, such as AKI.[49–51] Excessive activation of NLRP3 can potentially worsen renal injury, while suppressing NLRP3 activity can ameliorate renal injury.[52]

Figure 7. (A) An overall summary of interactions between ER stress and NLRP3 inflammasome. (B) An overall summary of interactions between ER stress and ROS. ER = endoplasmic reticulum, NLRP3 = activation of the NLR family pyrin domain containing 3, ROS = reactive oxygen species.

TLR4-NF-κB pathway was proven to participated in LPS-induced acute kidney injury through activating NLRP3 inflammasome pathway.[53] Bovine serum albumin can activate the NLRP3 inflammasome, while taurine-conjugated chemical chaperone ursodeoxycholic acid stops progression by reducing ER stress and improving kidney damage.[54] Furthermore, taurine-conjugated ursodeoxycholic acid prevents activation of the NLRP3 inflammasome in aldosterone-induced AKI by alleviating ER stress.[55] These results indicate that ER stress regulates the activation of the NLRP3 inflammasome. However, more studies may be needed to elucidate the specific mechanism by which ER stress controls NLRP3 inflammasomes in AKI.

Secondly, ER stress interplays with reactive oxygen species (ROS) in regulating the progress of AKI (Fig. 7B). Redox signaling is characterized by the intricate process through which physiological concentrations of reactive oxygen species are utilized to modify specific proteins reversibly, thus conveying essential information.[56] Maintaining cellular physiological homeostasis is crucial, as any prolonged deviation from redox equilibrium can result in ER stress.[57–59] It has been shown that ROS as the upstream trigger controls ER stress and other various signaling pathways that contribute to tubular cell damage in acute kidney injury.[60] Also, ROS inspires ER stress through targeting ER based calcium (Ca2+) signaling. ROS increases production of the inositol-1,4,5-trisphosphate, which binds and activates inositol-1,4,5-trisphosphate receptors 1 to 3 at the ER membrane to trigger Ca2+-release from the ER lumen, therefore inducing ER stress.[61,62]

However, ER stress also in turn exacerbates ROS production.[63] In ER, the folding of nascent peptides accompanied by the formation of disulfide bonds is called oxidative protein folding.[64] ER oxidase 1 and protein disulfide isomerase (PDI) are crucial components of the oxidative protein folding. Two mechanisms have been proposed for ROS generation during disulfide bond formation. First, ROS are formed as a byproduct when ER oxidase 1 utilizes oxygen to oxidize PDI. As a soluble protein in the ER, PDI catalyzes disulfide bonds between proteins and repairs incorrectly formed disulfide bonds.[65] Thus, proteins with multiple disulfide bonds may be more susceptible to generating higher levels of ROS. The second mechanism argues that ROS are generated by unfolded proteins independent of the formation of disulfide bonds. Accordingly, accumulation of unfolded proteins in the ER elicits Ca2+ leakage into the cytosol, increasing ROS production. It is of note, however, ER stress participates in the generation of ROS mediated by nicotinamide adenine dinucleotide phosphate oxidase 4, UPR activation induces an increase in level of nicotinamide adenine dinucleotide phosphate oxidase 4, which causes an increase in ROS generation.[66] Furtherly, the intracellular accumulation of ROS exceeds the cell’s antioxidant capacity, disrupting cellular redox homeostasis and causing further tissue injury.[67] Experimental investigation shows that adiponectin could protect the kidney against chronic intermittent hypoxia-induced injury through inhibiting ROS-related ER stress.[68] Thus, deciphering the functional interplays between ER stress, redox regulation and ROS in AKI will be a very worthwhile thing.

Recently, ferroptosis have become a focus of intense research and been considered as a potential therapeutic target for AKI. Interestingly, there is a close relationship between ER stress and ferroptosis. On the one hand, ferroptosis inducer erastin and artesunate trigger the unfolded protein response and ER stress.[69,70] Scott J Dixo’s study suggested that the upregulation of ER stress markers such as ATF4 and phosphorylation of eIF2α have been observed in ferroptosis.[71] The abnormal iron metabolism also participates in the occurrence of ER stress, iron limitation and inhibition of lipid ROS accumulation could suppress the ERS-induced body injury.[72] On the other hand, ER is the source of lipids for most membranes in other organelles and may also be critical to ferroptosis initiation.[73] Studies have found that ER stress can cause Fe2+ accumulation and lipid peroxidation through the PERK-Nrf2-HO-1 pathway, thereby causing ferroptosis.[74,75] In the PERK-ATF4 pathway of ER stress, ATF4 activation enables HSP5A to combine with GPX4 to form a complex, inhibiting the degradation of GPX4 and ferroptosis. PERK pathway can inhibit the generation of system xc-through the p53 gene to reduce the synthesis of GSH and ultimately promote ferroptosis.[76] Studies have revealed that ER stress might be a trigger for ferroptosis in cadmium-exposed renal tubular cells.[77] Cofilin-1 as a biomarker in the early diagnosis of AKI might induce AKI via promoting ER stress-mediated ferroptosis.[78] All above research demonstrated that the combined treatment targeting ER stress and ferroptosis may a novel therapeutic strategy for AKI.

In summary, current studies have shown that ER stress plays an important role in the regulation of AKI. In addition, the current research focus is that ER affect AKI through targeting inflammation and redox pathway. Of course, it is necessary to explore other pathways of ER regulating AKI and the relationship between various pathways at the molecular level.

Author contributions

Conceptualization: Pengkai Wang, Rui Yang.

Writing – original draft: Yuan Yang.

Writing – review & editing: Fang Yuan, Debiao Xiang, Pengkai Wang, Rui Yang, Xin Li.

Abbreviations:

AKI acute kidney injury

ATF6 activating transcription factor 6

ER endoplasmic reticulum

IRE1 inositol-requiring enzyme-1

NLRP3 activation of the NLR family pyrin domain containing 3

PDI protein disulfide isomerase

PERK protein kinase RNA PKR-like ER-resident kinase

ROS reactive oxygen species

UPR unfolded protein response

WOS Web of Science

This research paper is supported by the Hunan Provincial Key Laboratory of Anti-Resistance Microbial Drugs (No: 2023TP1013); the Changsha Science and Technology Project (No: kq2208464, kq2208463).

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.

How to cite this article: Yang Y, Yuan F, Xiang D, Wang P, Yang R, Li X. Spotlight on endoplasmic reticulum stress in acute kidney injury: A bibliometric analysis and visualization from 1997 to 2024. Medicine 2024;103:36(e39567).
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