Prevalence of angiotensin II type 1 receptor (AT1R)–activating autoantibodies in primary aldosteronism

Abstract

Background Autoantibodies to the angiotensin II type 1 receptor (AT1R) have been reported in patients with primary aldosteronism including aldosterone producing adenoma (APA) and idiopathic adrenal hyperplasia (IAH). Methods and Results Sera from 25 primary aldosteronism subjects (12 with IAH and 13 with APA) and 15 normotensive control subjects were assayed for AT1R autoantibodies by ELISA and an AT1R-transfected cell-based bioassay. Nine of 12 IAH subjects (75%) and 6 of 13 APA subjects (46%) were positive for AT1R autoantibodies in the bioactivity assay. The mean AT1R autoantibody activity for the IAH and APA subjects was significantly greater than controls (P<0.001 and P<0.01, respectively), and this in vitro activity was suppressed by the AT1R blocker losartan. None of the controls had significant AT1R autoantibody activity. ELISA values were less sensitive but were positive in some subjects with IAH and APA. The mean arterial pressure of these primary aldosteronism subjects correlated modestly with AT1R autoantibody activity. Conclusion These data confirm the presence of active AT1R autoantibodies in a high percentage of subjects with primary aldosteronism irrespective of their underlying etiology. These observations have both pathophysiological and clinical implications.

Primary Aldosteronism: Changing Definitions and New Concepts of Physiology and Pathophysiology Both Inside and Outside the Kidney

“…Furthermore, plasma aldosterone levels fell to a greater degree after captopril administration in AT1AA-positive compared with AT1AA-negative PA patients, suggesting a functional role in terms of promoting aldosterone secretion. Li et al (285) detected AT1AA by an AT1 receptor-transfected cell-based bioassay in 9 of 12 patients with BAH and 6 of 13 with APA but in none of 15 normotensive control subjects (285). In vitro studies performed by this group showed that the AT1AA directly stimulated basal and enhanced ANG II-induced aldosterone production by cultured adrenal cells in an AT1 receptor-dependent manner (as evidenced by blockade of these effects with candesartan) (259).…”

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

“…7, 8 These autoantibodies were initially identified in a limited number of subjects, but this list has expanded rapidly in the last few years in several hypertensive-related conditions such as preeclampsia, 9 malignant and refractory hypertension, 10, 11 renal allograft rejection, 12 and more recently with primary aldosteronism. 13–15 There is no currently published information as to whether activating autoantibodies to the AT2R exist; and whether they might alter the complex role of Ang II in vascular homeostasis.…”

Genetic and Potential Autoimmune Triggers of Primary Aldosteronism

“…This predominance of the AT 1 -AA in the BAH subtype rather than the APA subtype is in direct contrast to the original findings. 20 Moreover, the APA and BAH subtypes with contrasting AT 1 -AA titers displayed similar blood pressure levels in 1 study, 20 whereas Li et al 22 described a modest correlation of AT 1 -AA functional activity with mean arterial pressure. However, the 2 studies used different assays to measure AT 1 -AA.…”

“…The AT 1 -AA-mediated production of aldosterone in the adrenal cell line was enhanced in the presence of low doses of angiotensin II, suggesting that the antibodies may alter the allosteric configuration of the AT 1 R and facilitate angiotensin II binding. 21 A follow-up study by the same group on a larger series of patients with PA demonstrated an increased prevalence in BAH compared with those with an APA (75% versus 46%) 22 (Table). This predominance of the AT 1 -AA in the BAH subtype rather than the APA subtype is in direct contrast to the original findings.…”

“…Rossitto et al 20 used an ELISA-based assay, whereas Kem et al 21 and Li et al 22 used cell-based functional assays; in fact, in a direct comparison, the 2 types of assay give widely different results. 22 However, the inconsistency surrounding the prevalence of AT 1 -AA in patients with PA should be resolved using large cohorts of patients with PA who have been accurately subtyped according to strict criteria 23 and using extensive controls including patients with preeclampsia as positive controls in reliable functional assays. The reported increased prevalence of AT 1 -AA in patients with BAH is of potential relevance to the distinct phenotypes of adrenal sensitivity to angiotensin II of patients with BAH and APA.…”