Abstract 280: Modulation of Aldosterone Synthesis in Human Adrenocortical Cells by Estrogens via an Interaction on Beta Estrogen and Gpr30 Receptor Subtypes

Background and aim. The gender dimorphism in the pressor effect of hyperaldosteronism suggests that estrogens may modulate aldosterone synthesis. Estrogens were suggested to affect adrenocortical cell proliferation via beta estrogen receptor (ERβ), but it remains unknown if they also influence aldosterone synthesis. Methods. We therefore investigated the expression of alpha (ERα), ERβ and of G protein-coupled receptor (GPR)30 in HAC15 cells, a human adrenocortical carcinoma cell line. HAC15 cells were stimulated with 10 -7 M 17β-estradiol (E2) alone, or with a selective ERβ antagonist (10 -5 M; Tetrahydrochrysenediol THC), a selective ERα antagonist (10 -5 M; MPP dihydrochloride), a non selective ERα and ERβ antagonist (10 -5 M; ICI 182.780 fulvestrant), a selective GPR30 receptor antagonist (10 -5 M; G-15). The cells were also exposed to the highly selective GPR30 agonist G-1, alone or in the presence of MPP, or THC, or Fulvestrant and G-15. CYP11B2 mRNA expression was measured with quantitative real time RT-PCR (Universal Probe Library Roche). Results. The three estrogen receptor subtypes were found to be expressed at different levels (ERβ>>ERα=GPR30) in HAC15 cells. E2 alone or on top of selective ERα antagonism did not alter CYP11B2 expression. At variance, E2 on top of selective ERβ antagonism, or of combined ERβ and ERα antagonism, caused a 5- to 7- fold upregulation of CYP11B2 mRNA, a finding that was replicated by the exposure of cells to G-1 on top of combined ERβ and ERα blockade. Conclusions . 1) GPR30 is expressed in human adrenocortical cells at levels that are comparable to ERα, but less abundatly than ERβ subtype receptor. 2) 17β-estradiol activates CYP11B2 synthesis via an interaction between ERβ blockade and GPR30 activation. Hence, by showing a role for estrogens in the regulation of aldosterone synthesis via GPR30 subtype receptor, these results could account for the diverse pressor effects of excess aldosterone in men and in fertile vs post-menopausal women.