Aldosterone-Regulating Receptors and Aldosterone-Driver Somatic Mutations

Front Endocrinol (Lausanne). 2021 Mar 16:12:644382. doi: 10.3389/fendo.2021.644382. eCollection 2021.

Abstract

Background: Somatic 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.

Objective: To 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.

Methods: RNA 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.

Results: Compared 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.

Conclusions: While 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.

Keywords: adrenal; adrenal cortex; adrenocorticotropic hormone (ACTH); aldosterone; angiotensin; primary aldosteronism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma
  • Adrenal Glands / metabolism
  • Adrenocorticotropic Hormone / metabolism*
  • Adult
  • Aged
  • Aldosterone / metabolism*
  • Female
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / biosynthesis
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Middle Aged
  • Mutation*
  • Real-Time Polymerase Chain Reaction
  • Receptor, Angiotensin, Type 1 / biosynthesis*
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Melanocortin, Type 2 / biosynthesis*
  • Receptor, Melanocortin, Type 2 / genetics
  • Receptors, Corticotropin / metabolism
  • Steroid 11-beta-Hydroxylase / biosynthesis
  • Steroid 11-beta-Hydroxylase / genetics
  • Steroid 17-alpha-Hydroxylase / biosynthesis
  • Steroid 17-alpha-Hydroxylase / genetics
  • Young Adult

Substances

  • AGTR1 protein, human
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNJ5 protein, human
  • MRAP protein, human
  • Membrane Proteins
  • Receptor, Angiotensin, Type 1
  • Receptor, Melanocortin, Type 2
  • Receptors, Corticotropin
  • Aldosterone
  • Adrenocorticotropic Hormone
  • CYP17A1 protein, human
  • Steroid 17-alpha-Hydroxylase
  • Steroid 11-beta-Hydroxylase