
Aldosterone Stimulates Its Biosynthesis Via A Novel GPER Mediated Mechanism.
Authors of this article are:
Caroccia B, Seccia TM, Piazza M, Prisco S, Zanin S, Iacobone M, Lenzini L, Pallafacchina G, Domening O, Poglitsch M, Rizzuto R, Rossi GP.
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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. As 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 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 endpoints. Similar experiments were repeated in strips obtained ex vivo from aldosterone-producing adenoma 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, as 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-AT-1R heterodimerization.CONCLUSION: We propose that this autocrine-paracrine mechanism could enhance aldosterone biosynthesis under conditions of immediate physiological need where the renin-angiotensin-aldosterone system is stimulated as, for example, hypovolemia. Moreover, as aldosterone-producing adenoma overexpresses GPER this mechanism could contribute to the aldosterone excess that occurs in primary aldosteronism in a seemingly autonomous fashion from angiotensin II.Copyright © 2019 Endocrine Society.
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