Aldosterone-Regulating Receptors and Aldosterone-Driver Somatic Mutations

Frontiers in Endocrinology

Juilee Rege¹  Samuel W. Plaska¹  Jung Soo Lim²  William E. Rainey³  Adina F. Turcu³ 

[1] Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States;Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju Severance Christian Hospital, Wonju, South Korea;Division of Metabolism, Endocrine, and Diabetes, University of Michigan, Ann Arbor, MI, United States;

关键词: primary aldosteronism;    aldosterone;    angiotensin;    adrenocorticotropic hormone (ACTH);    adrenal;    adrenal cortex;   

DOI  :  10.3389/fendo.2021.644382

来源: DOAJ

【 摘 要 】

BackgroundSomatic gene mutations that facilitate inappropriate intracellular calcium entrance have been identified in most aldosterone-producing adenomas (APAs). Studies suggest that angiotensin II and adrenocorticotropic hormone (ACTH) augment aldosterone production from APAs. Little is known, however, regarding possible variations in response to hormonal stimuli between APAs with different aldosterone-driver mutations.ObjectiveTo analyze the transcript expression of type 1 angiotensin II receptors (AGTR1), ACTH receptors (MC2R), and melanocortin 2 receptor accessory protein (MRAP) in APAs with known aldosterone-driver somatic mutations.MethodsRNA was isolated from APAs with mutations in: KCNJ5 (n = 14), ATP1A1 (n = 14), CACNA1D (n = 14), and ATP2B3 (n = 5), and from normal adjacent adrenal tissue (n = 45). Transcript expression of MC2R, MRAP, AGTR1, aldosterone synthase (CYP11B2), 17α-hydroxylase/17,20-lyase (CYP17A1), and 11β-hydroxylase (CYP11B1) were quantified using quantitative RT-PCR and normalized to β-actin.ResultsCompared to adjacent normal adrenal tissue, APAs had higher transcript levels of CYP11B2 (2,216.4 [1,112.0, 2,813.5]-fold, p < 0.001), MC2R (2.88 [2.00, 4.52]-fold, p < 0.001), and AGTR1 (1.80 [1.02, 2.80]-fold, p < 0.001]), and lower transcript levels of MRAP, CYP17A1, and CYP11B1 (0.28–0.36, p < 0.001 for all). MC2R and CYP11B2 transcripts were lower in APAs with KCNJ5 vs. other mutations (p < 0.01 for both). MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, and with MRAP expression in APAs harboring ATPase mutations.ConclusionsWhile MC2R and AGTR1 are expressed in all APAs, differences were observed based on the underlying aldosterone-driver somatic mutations. In tandem, our findings suggest that APAs with ATPase-mutations are more responsive to ACTH than KCNJ5-mutated APAs.

【 授权许可】

Unknown