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Estrogen Regulates Adrenal Angiotensin AT₁ Receptors by Modulating AT₁ Receptor Translation

Departments of Physiology and Biophysics (Z.W., K.S.) and Medicine (C.M., D.M.R., W.Z., J.G.V., K.S.), Georgetown University, Washington, D.C. 20007

Address all correspondence and requests for reprints to: Kathryn Sandberg, Ph.D., Building D, Room 394, Georgetown University Medical Center, 4000 Reservoir Road, NW, Washington, D.C. 20007. E-mail: sandberg{at}georgetown.edu

Hypertension and associated cardiovascular disease increase after menopause. Angiotensin AT₁ receptor (AT₁R) antagonists are effective treatments, in part, by inhibiting angiotensin II (Ang II)-induced aldosterone release from the adrenal zona glomerulosa (ZG). Estrogen decreases the number of AT₁Rs in the adrenal gland and attenuates acute Ang II-induced aldosterone release. Here, we examined the effects of 17ß-estradiol (E₂) on AT₁R gene regulation in the rat adrenal cortex (AC). Female rats were ovariectomized and injected with vehicle or E₂. Immunohistochemistry revealed the presence of both estrogen receptor (ER) and ERß in the ZG, and E₂ treatment increased the intensity of their nuclear staining. Under conditions in which AT₁R maximal binding capacity was decreased by 46%, chronic miniosmotic pump Ang II-induced aldosterone secretion was reduced by 43%. E₂ treatment had no effect on AT_1aR and AT_1bR mRNA levels in the AC, whereas the AT₁R mRNA polysome distribution in sucrose gradients was shifted to lighter fractions, indicating that E₂ treatment reduces AT₁R translation. RNA binding proteins (RBPs) in AC extracts formed complexes with the 5' leader sequence (5'LS), coding region, and the 3'-untranslated region (3'UTR); however, only the activity of 5'LS RBPs was regulated by E₂ treatment. These data suggest that E₂, acting through its receptors in the ZG, reduces AT₁R density and Ang II-induced aldosterone release, primarily by inhibiting AT₁R translation, possibly by blocking ribosomal scanning caused by increased steric hindrance from 5'LS RBPs. Dysregulation of this posttranscriptional mechanism may contribute to the increased incidence of cardiovascular disease associated with menopause.

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