Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production

Abstract

AbstractThe 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 inWNT2Band 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 ofWnt2bin the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboringWNT2Bloss-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.HighlightsWNT2Bvariant is associated with increased risk for primary aldosteronismWnt2bknock-out mice show defects in adrenal morphologyWnt2bknock-out mice have hyperreninemic hypoaldosteronismWNT2B activates non-canonical Wnt/planar cell polarity signalingWNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism