Aldosterone Stimulates Its Biosynthesis Via a Novel GPER-Mediated Mechanism

J Clin Endocrinol Metab. 2019 Dec 1;104(12):6316-6324. doi: 10.1210/jc.2019-00043.


Context: The G protein-coupled estrogen receptor (GPER) mediates an aldosterone secretagogue effect of 17β-estradiol in human HAC15 adrenocortical cells after estrogen receptor β blockade. Because GPER mediates mineralocorticoid receptor-independent aldosterone effects in other cell types, we hypothesized that aldosterone could modulate its own synthesis via GPER activation.

Methods: HAC15 cells were exposed to aldosterone in the presence or absence of canrenone, a mineralocorticoid receptor antagonist, and/or of the selective GPER antagonist G36. Aldosterone synthase (CYP11B2) mRNA and protein levels changes were the study end points. Similar experiments were repeated in strips obtained ex vivo from aldosterone-producing adenoma (APA) and in GPER-silenced HAC15 cells.

Results: Aldosterone markedly increased CYP11B2 mRNA and protein expression (vs untreated samples, P < 0.001) in both models by acting via GPER, because these effects were abolished by G36 (P < 0.01) and not by canrenone. GPER-silencing (P < 0.01) abolished the aldosterone-induced increase of CYP11B2, thus proving that aldosterone acts via GPER to augment the step-limiting mitochondrial enzyme (CYP11B2) of its synthesis. Angiotensin II potentiated the GPER-mediated effect of aldosterone on CYP11B2. Coimmunoprecipitation studies provided evidence for GPER-angiotensin type-1 receptor heterodimerization.

Conclusion: We propose that this autocrine-paracrine mechanism could enhance aldosterone biosynthesis under conditions of immediate physiological need in which the renin-angiotensin-aldosterone system is stimulated as, for example, hypovolemia. Moreover, as APA overexpresses GPER this mechanism could contribute to the aldosterone excess that occurs in primary aldosteronism in a seemingly autonomous fashion from angiotensin II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex Neoplasms / drug therapy
  • Adrenal Cortex Neoplasms / metabolism*
  • Adrenal Cortex Neoplasms / pathology
  • Adrenocortical Adenoma / drug therapy
  • Adrenocortical Adenoma / metabolism*
  • Adrenocortical Adenoma / pathology
  • Aldosterone / biosynthesis
  • Aldosterone / pharmacology*
  • Benzodioxoles / pharmacology
  • Calcium / metabolism
  • Canrenone / pharmacology
  • Cytochrome P-450 CYP11B2 / genetics
  • Cytochrome P-450 CYP11B2 / metabolism*
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Mineralocorticoid Receptor Antagonists / pharmacology
  • Quinolines / pharmacology
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptors, Estrogen / antagonists & inhibitors
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Renin-Angiotensin System / drug effects
  • Tumor Cells, Cultured


  • Benzodioxoles
  • G36 compound
  • GPER1 protein, human
  • Mineralocorticoid Receptor Antagonists
  • Quinolines
  • Receptor, Angiotensin, Type 1
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • Aldosterone
  • Canrenone
  • Cytochrome P-450 CYP11B2
  • Calcium