title: Autoimmune mechanisms activating the angiotensin AT1 receptor in 'primary' aldosteronism.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Endocrinology (D.C.K., H.L., C.L., M.V.-W., A.G., M.K., C.Z., A.B., V.R., X.Y.), Heart Rhythm Institute (D.C.K., H.L., X.Y.), and Department of Microbiology and Immunology (M.W.C.), University of Oklahoma Health Sciences Center and Veterans Affairs Medical Center, Oklahoma City, Oklahoma 73104; and G. V. (Sonny) Montgomery Veterans Affairs Medical Center and University of Mississippi Medical Center (C.V.-M., C.E.G.-S.), Jackson, Mississippi 39216.
authors.forename: David C
authors.initials: DC
authors.lastname: Kem
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
authors.forename: Carolina
authors.initials: C
authors.lastname: Velarde-Miranda
authors.forename: Campbell
authors.initials: C
authors.lastname: Liles
authors.forename: Megan
authors.initials: M
authors.lastname: Vanderlinde-Wood
authors.forename: Allison
authors.initials: A
authors.lastname: Galloway
authors.forename: Muneer
authors.initials: M
authors.lastname: Khan
authors.forename: Caitlin
authors.initials: C
authors.lastname: Zillner
authors.forename: Alexandria
authors.initials: A
authors.lastname: Benbrook
authors.forename: Veitla
authors.initials: V
authors.lastname: Rao
authors.forename: Celso E
authors.initials: CE
authors.lastname: Gomez-Sanchez
authors.forename: Madeleine W
authors.initials: MW
authors.lastname: Cunningham
authors.forename: Xichun
authors.initials: X
authors.lastname: Yu
mesh_terms: D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects; D001323:Autoantibodies / Q000276:immunology*; D015551:Autoimmunity / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D006929:Hyperaldosteronism / Q000276:immunology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan