SAT-LB90 Angiotensin II and ACTH Receptor Expression in Aldosterone-Producing Adenomas

Abstract

Background: The mechanisms leading to elevated aldosterone synthesis in aldosterone-producing adenomas (APAs) remain an area of active research. Aldosterone-driver somatic gene mutations that allow inappropriate intracellular calcium entrance have been identified in most APAs. Cell-based studies of such mutations indicate that responses to physiologic stimuli, such as angiotensin II or ACTH, are increased. Little is known, however, regarding possible variations in response to hormonal stimuli between APAs with different aldosterone-driver mutations. Herein, we analyzed the transcript expression of the ACTH receptor (MC2R), the melanocortin 2 receptor accessory protein (MRAP) and the type 1 angiotensin II receptor (AGTR1) in APAs with known aldosterone-driver somatic mutations. Methods: RNA was isolated from normal adrenal glands (n=8), and from APAs with mutations in: KCNJ5 (n=14), ATP1A1 (n=14), CACNA1D (n=14), and ATP2B3 (n=5). The gene expressions of MC2R, MRAP, AGTR1 and aldosterone synthase (CYP11B2) were quantified using qPCR and normalized to β-actin. Results: All APA mutation groups had significantly higher transcript levels of CYP11B2, MC2R and AGTR1 as compared to whole normal adrenals. While MRAP and AGTR1 transcripts were comparable between tumor mutation groups, MC2R expression was significantly lower in KCNJ5-mutated APAs compared to other APAs. Overall, CYP11B2 expression demonstrated positive correlations with MC2R (R=0.728, p<0.0001) and AGTR1 (R=0.397, p=0.006) in APAs. These correlations were strongest in APAs harboring ATP1A1 mutations, and weakest in KCNJ5-mutated APAs. Conversely, CYP11B2 did not correlate with MC2R and AGTR1 in the normal adrenals. Conclusions: ACTH and angiotensin II receptors are expressed in all APAs, regardless of the underlying aldosterone-driver somatic mutations. Further research to clarify the effects of ACTH and posture on aldosterone production from APAs could provide additional insight into developing diagnostic and subtyping tools for primary aldosteronism.