Hong Ji, MD
Department of Physiology & Biophysics
Basic Science Building, Rm 235B
3900 Reservoir Road, NW
Washington, DC 20057
Phone: 202 687-8267
Fax: 202 687-7407
Gonadal steroid regulation of angiotensin receptors
Much data indicates that estrogen has a regulatory influence on various components of the renin angiotensin system (RAS). In postmenopausal women receiving estrogen, renin levels are significantly lower compared to age-matched men and to women not on estrogen replacement therapy. The circulating levels of angiotensin II (Ang II) in ovariectomized (OVX) rats are reduced by estrogen treatment and estrogen significantly decreases the levels of angiotensin converting enzyme (ACE) and circulating Ang II in the hypertensive renin transgenic rat. These effects of estrogen on renin, angiotensinogen, ACE and circulating Ang II ultimately alter the activity of the angiotensin type 1 (AT1) receptor, the mediator of Ang II action, on fluid homeostasis and blood pressure control. Both ACE inhibitors and AT1 receptor antagonists are clinically effective treatments for hypertension and cardiovascular disease, suggesting that overactivity of the RAS is a significant risk factor for these pathological disease states. Interestingly, a second highly recognized factor implicated in the pathogenesis of hypertension, atherosclerosis, congestive heart failure and associated reno-cardiovascular disease is estrogen deficiency. Previously, we have found that the E2 replacement in ovariectomized (OVX) rats markedly decreased AT1 receptor number (Bmax) in the pituitary, adrenal and aorta compared to controls (OVX + vehicle) and under these conditions, E2 decreased Ang II-induced aldosterone production. These indicate that estrogen significantly down-regulates both adrenal AT1 receptor binding and functional effects of RAS stimulation, specifically Ang II-mediated aldosterone secretion. These findings suggest that a defect in the ability of E2 to reduce the number and therefore activity of the AT1 receptor in the kidney of the Dahl salt sensitive rat (DS) animal contributes to the differences in the degree of OVX-induced hypertension between DS and Dahl salt resistant rat (DR). The fact that estrogen is able to regulate AT1 receptors in the DS rat adrenal but not in the DS kidney emphasizes the growing appreciation for the complexity and multifaceted nature of estrogen action in cardiovascular and renal physiology. Mechanisms that link estrogen to activity of the RAS are of relevance to understanding the role of estrogen replacement therapy in postmenopausal women who are at risk for cardiovascular and kidney disease.
- Sandberg, K. and H. Ji, “Kidney angiotensin receptors and their role in renal pathophysiology,” Sem. Nephrol., 20:402-416, 2000.
- Zheng, W., Ji, H., Szabo, Z., Brown, P.R., Yoo, S-S. and K. Sandberg, “Coordinate regulation of canine glomeruli and adrenal angiotensin receptors by dietary sodium manipulation”, Kidney Int., 59:1881-1890, 2001.
- Sandberg, K., Wu Z., Ji, H., Hernandez E. and S. Mulroney, “Regulation of G-protein coupled receptor cytosolic mRNA binding proteins,” in: RNA Binding Proteins: New Concepts in Gene Regulation, K. Sandberg & S. Mulroney, Eds., Boson: Kluwer Academic Publishers, pp285-306, 2002.
- Ji, H., Wu, Z., Zheng, W., Maric, C., Speth, R.C. and K. Sandberg, “Abnormal estrogen regulation of the renal AT1 receptor in the Dahl salt sensitive rat,” submitted.
- Mok, K-Y., Sandberg, K., Zheng, W., Pesce, C., Menini, S., Mulroney, S and H. Ji, “Effect of gonadal steroids on renal injury in the renal wrap model of progressive renal disease” submitted.