
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.08.23.609423
preprint
1
Article
Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production
Borges Kleiton S. http://orcid.org/0000-0003-0356-922X

Little Donald W.
de Almeida Magalhães Taciani
Ribeiro Claudio
Dumontet Typhanie
Lapensee Chris
Basham Kaitlin J.
Seth Aishwarya
Azova Svetlana
Guagliardo Nick A.
Barrett Paula Q.
Berber Mesut
O’Connell Amy E.
Turcu Adina F.
Lerario Antonio Marcondes
Mohan Dipika R.
Rainey William
Carlone Diana L. http://orcid.org/0000-0001-6935-0189

Hirschhorn Joel N.
Salic Adrian
Breault David T.
Hammer Gary D.
24 8 2024
2024.08.23.609423https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.08.23.609423
nihpp-2024.08.23.609423.pdf
Abstract

The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant in WNT2B and an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss of Wnt2b in the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboring WNT2B loss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications.

Highlights

WNT2B variant is associated with increased risk for primary aldosteronism

Wnt2b knock-out mice show defects in adrenal morphology

Wnt2b knock-out mice have hyperreninemic hypoaldosteronism

WNT2B activates non-canonical Wnt/planar cell polarity signaling

WNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism
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pmc
