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J Clin Endocrinol Metab. 2019 May 24. pii: jc.2019-00043. doi: 10.1210/jc.2019-00043. [Epub ahead of print]

Aldosterone Stimulates Its Biosynthesis Via A Novel GPER Mediated Mechanism.

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Specialized Center for Blood Pressure Disorders-Regione Veneto and Hypertension Unit, Department of Medicine-DIMED, University of Padua, Padua, Italy.
Endocrine Surgery Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy.
Department of Biomedical Sciences, University of Padua, Padua, Italy.
Italian National Research Council (CNR), Neuroscience Institute, Padua.
Attoquant Diagnostics, Vienna, Austria.



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.


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.


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.


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.


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