OC6.2 - ECE_3237 - Role of the mineralocorticoid receptor in the physiology of the adrenal cortex and the development of aldosterone producing adenomas

Background Primary aldosteronism (PA) is a major cause of secondary arterial hypertension, characterized by autonomous aldosterone production. The mineralocorticoid receptor (MR) binds aldosterone and is expressed in the adrenal cortex specifically in the zona glomerulosa (ZG) and in aldosterone-producing adenomas. Given the role of MR in tissue remodeling and its expression in aldosterone-producing cells, we hypothesized that MR could be involved in the pathophysiology of PA through autocrine-paracrine mechanisms. Objectives To define the cell-autonomous roles of MR in aldosterone-producing cells using ZG-specific MR knockout mice combined with single-nucleus transcriptomics. Methods We generated Cyp11b2-Cre-driven MR knockout (MRKOAd) mice and performed morphological, hormonal and molecular phenotyping under standard and low-salt diets. Single-nucleus RNA sequencing (snRNAseq) across four conditions was analyzed to define population-specific MR functions and plasticity mechanisms. Results MR deletion reduced Cyp11b2 and aldosterone synthase (AS) expression in the adrenal cortex, with sex-specific effects on ZG architecture, but no change in basal aldosterone levels. This was associated with reduced proliferation and PKA activation, without modification of Wnt/β-catenin signaling. Under low salt diet, increased aldosterone production was accompanied by ZG expansion and increased AS expression in wild type mice, which was abolished in MRKOAd mice of both sexes. snRNAseq analysis revealed three mechanistically distinct plasticity programs following LSD: (1) ZG maintained identity through MR-dependent proliferation; (2) ZG_ZF transition zone showed robust plasticity driven by environmental signals (10% MR-dependent); and (3) zona fasciculata resolved into two subpopulations - ZF1 underwent authentic MR-dependent ZG transdifferentiation supported by constitutive metabolic priming, while ZF2 showed Cyp11b2 induction without acquiring ZG identity. MR-dependent genes, representing 28% of plasticity genes, accounted for 69% of functional ZG signature changes and converged on metabolic pathways (oxidative phosphorylation, ATP synthesis, steroid biosynthesis), establishing MR as an orchestrator of metabolic reprogramming. Conclusions MR plays distinct, cell-population-specific roles across the adrenal cortex. MR maintains ZG function in an autocrine-paracrine loop under basal conditions and regulates proliferative capacity, ZG architecture sex-specifically, and orchestrates metabolic transformation required for adrenal cortex plasticity following a salt challenge.