title: GPER-1 and estrogen receptor-β ligands modulate aldosterone synthesis.
abstract: Fertile women have lower blood pressure and cardiovascular risk than age-matched men, which suggests that estrogens exert cardiovascular protective effects. However, whether 17 β-estradiol (E2) blunts aldosterone secretion, and thereby affects the gender dimorphism of blood pressure, is unknown. We therefore sought for the estrogen receptor (ER) subtypes in human adrenocortical tissues ex vivo by performing gene and protein expression studies. We also investigated the effect of E2 on aldosterone synthesis and the involved receptors through in vitro functional experiments in the adrenocortical cells HAC15. We found that in the human adrenal cortex and aldosterone-producing adenoma cells, the most expressed ERs were the ERβ and the G protein-coupled receptor-1 (GPER-1), respectively. After selective ERβ blockade, E2 (10 nmol/L) markedly increased both the expression of aldosterone synthase and the production of aldosterone (+5- to 7-fold vs baseline, P < .001). Under the same condition, the GPER-1 receptor agonist 1-[4-(6-bromo-benzo (1, 3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c] quinolin-8-yl]-ethanone (G-1) (10 nmol/L) mimicked this effect, which was abrogated by cotreatment with either the GPER-1 receptor antagonist (3aS*,4R*,9bR*)-4-(6-Bro-mo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta[c]quinoline (G-15), or a selective protein kinase A inhibitor 8-Bromo-2-monobutyryladenosine-3,5-cyclic mono-phosphorothioate, Rp-isomer. Silencing of the ERβ significantly raised aldosterone synthase expression and aldosterone production. Conversely, silencing of the GPER-1 lowered aldosterone synthase gene and protein expression. Moreover, it blunted the stimulatory effect of E2 on aldosterone synthase that was seen during ERβ blockade. These results support the conclusion that in humans, E2 inhibits aldosterone synthesis by acting via ERβ. Pharmacologic disinhibition of ERβ unmasks a potent secretagogue effect of E2 that involves GPER-1 and protein kinase A signaling.
authors.affiliation: Internal Medicine 4 (B.C., T.M.S., A.G.C., F.G., M.K., G.C., E.G., S.M., L.L., G.P.R.), Department of Medicine-DIMED, University of Padua, Padua 35126, Italy; and Surgical Pathology and Cytopathology Unit (F.S., A.F.), Department of Medicine, University of Padua, Padua 35126, Italy.
authors.forename: Brasilina
authors.initials: B
authors.lastname: Caroccia
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Seccia
authors.forename: Abril Gonzalez
authors.initials: AG
authors.lastname: Campos
authors.forename: Francesca
authors.initials: F
authors.lastname: Gioco
authors.forename: Maniselvan
authors.initials: M
authors.lastname: Kuppusamy
authors.forename: Giulio
authors.initials: G
authors.lastname: Ceolotto
authors.forename: Eugenia
authors.initials: E
authors.lastname: Guerzoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Simonato
authors.forename: Sara
authors.initials: S
authors.lastname: Mareso
authors.forename: Livia
authors.initials: L
authors.lastname: Lenzini
authors.forename: Ambrogio
authors.initials: A
authors.lastname: Fassina
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Rossi
mesh_terms: D000302:Adrenal Cortex / Q000378:metabolism; D000450:Aldosterone / Q000096:biosynthesis*; D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007223:Infant; D008024:Ligands; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D047629:Estrogen Receptor beta; C109584:GPER1 protein, human; D008024:Ligands; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D000450:Aldosterone; D004958:Estradiol