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Submitted on January 6, 2003
Accepted on March 26, 2003
1 Departments of Physiology & Biophysics and Medicine, Georgetown University, Washington, DC 20007
* To whom correspondence should be addressed. E-mail: sandberg{at}georgetown.edu.
Hypertension and associated cardiovascular disease increases 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 17
-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 ER
and ER estrogen receptors in the ZG and E2-treatment increased the intensity of their nuclear staining. Under conditions in which AT1R Bmax was decreased by 46%, chronic mini-osmotic pump Ang II-induced aldosterone secretion was reduced by 43%. E2-treatment had no effect on AT1aR and AT1bR mRNA levels in the AC, whereas, the AT1R mRNA polysome distribution in sucrose gradients was shifted to lighter fractions, indicating E2 treatment reduces AT1R translation. RNA binding proteins (RBPs) in AC extracts formed complexes with the 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 due to increased steric hindrance from 5'LS RBPs. Dysregulation of this post-transcriptional mechanism may contribute to the increased incidence of cardiovascular disease associated with menopause.
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