Autoimmune Mechanisms Activating the Angiotensin AT1 Receptor in 'Primary' Aldosteronism

• Published in: The journal of clinical endocrinology and metabolism 2014-05, Vol.99 (5), p.1790-1797
• Main Authors: Kem, David C, Li, Hongliang, Velarde-Miranda, Carolina, Liles, Campbell, Vanderlinde-Wood, Megan, Galloway, Allison, Khan, Muneer, Zillner, Caitlin, Benbrook, Alexandria, Rao, Veitla, Gomez-Sanchez, Celso E, Cunningham, Madeleine W, Yu, Xichun
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Arterioles - drug effects; Autoantibodies - immunology; Autoimmunity - physiology; Cell Line, Tumor; Endocrine Research; Female; Humans; Hyperaldosteronism - immunology; Losartan - pharmacology; Male; Middle Aged; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Rats; Receptor, Angiotensin, Type 1 - immunology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-3282

Context: The mechanisms causing excessive aldosterone production and hypertension in primary aldosteronism (PA) are complex and often incompletely recognized. Autoantibodies to the angiotensin AT1 receptor (AT1R) have been reported in some PA patients with an aldosterone-producing adenoma but not with idiopathic adrenal hyperplasia. Objective: We investigated whether these autoantibodies will activate AT1R and thereby potentially contribute to the pathophysiology of PA. Design: AT1R autoantibody activity in sera and/or IgG purified from 13 biochemically confirmed PA patients was measured using AT1R-transfected cells, and their contractile effects were assayed using perfused rat cremaster arterioles. Aldosterone stimulation was measured in vitro using isolated human adrenal carcinoma (HAC15) adrenal cells. These data were compared with sera obtained from a group of normotensive control subjects who were expected to have negligible AT1R autoantibodies. Results: Sera from each of the 13 PA patients significantly increased AT1R activation in AT1R-transfected cells compared with 20 control subjects, and this activity was inhibited by the selective AT1R blocker losartan. Sera and IgG purified from AT1R autoantibody-positive sera demonstrated significant vasoconstrictive effects in isolated rat cremaster arterioles and were blocked by losartan. Moreover, the AT1R autoantibody-positive IgG directly stimulated aldosterone production in the cultured adrenal cells and enhanced angiotensin-induced aldosterone production in these cells, and these effects were blocked by candesartan. Conclusions: These data support a probable pathophysiological role for AT1R autoantibodies in PA and thereby raise important etiological and therapeutic implications.