The Evolution of Primary Aldosteronism and the Role of Norrin

Primary aldosteronism (PA) is renin-independent aldosterone production that causes hypertension and cardiovascular disease. We investigated the proteomic evolution of PA from normotensive people with renin-independent aldosteronism to those with overt PA. The PA plasma proteome was characterized by pathways related to cardiovascular disease (inflammation, energy/redox, vascular remodeling). We identified proteins exhibiting dose-dependent trends paralleling the continuum of renin-independent aldosterone production, then using adrenal vein proteomics, identified proteins exhibiting the archetypal pattern of unilateral PA (peak abundance in the dominant vein with suppression in the contralateral vein). Among these, Norrin, a Wnt/β-catenin ligand previously identified as a risk locus for PA by GWAS, was robustly validated using functional testing (ACTH- and angiotensin II-induced interventions, and correlations with 18-hybrid steroids) and genetic testing (dose-dependent associations with NDP SNPs). The evolution of PA originates in normotensive people, is characterized by proteomic signatures of cardiovascular disease, and Norrin is a novel regulator of PA pathophysiology.