The sexual dimorphism associated with many cardiovascular and renal diseases related to aging is well documented with the risks being significantly higher for men than women. Two of the major risk factors in these diseases are felt to be increased activity of the renin angiotensin system (RAS) and estrogen deficiency. Furthermore, there is accumulating evidence that estrogen may have a regulatory influence on the RAS. In view of its considerable potential physiologic and pathophysiologic significance, we propose to investigate how estrogen regulates the activity of the RAS. Specific hypotheses to be tested in the proposed studies are: 1) estrogen down- regulates the density of the type 1 angiotensin receptor subtype (AT1) expressed in adrenal and kidney tissues and thereby attenuates tissue responsiveness to the hormone, angiotensin II (Ang II); 2) estrogen mediates its effects on AT1 receptor AT1 receptor expression in these tissues via the estrogen type (3 (ERs) receptor; 3) estrogen has direct effects on AT1 receptor expression by modulating receptor transcriptional and/or posttranscriptional mechanisms; 4) estrogen also acts to decrease AT1 receptor expression by modulating the local production of Ang II; and 5) the ability of estrogen to down-regulate Ang II activity in the adrenal and kidney is attenuated in animal models of salt-sensitive hypertension and aging.
Our first aim i s to determine the effects of estrogen on AT1 receptor density in the adrenal and kidney of the rat using quantitative autoradiography under a variety of perturbations of the RAS.
In Aim 2, we will determine the effects of estrogen on adrenal and kidney tissue responsiveness to Ang II by measuring the effects of estrogen on Ang II-induced changes in aldosterone secretion and renal hemodynamics.
Our third aim will focus on determining the specific mechanisms by which estrogen reduces the density of AT1 receptors. We will examine the effect of estrogen on AT1 receptor synthetic and degradative pathways and examine its effects of on the components of the plasma and tissue RAS. We will also determine which estrogen receptor subtype mediates the effects of estrogen. In the last aim, we will study the effects of estrogen on adrenal and kidney AT1 receptor density and function in relevant animal models of salt-sensitive hypertension and aging. Our studies will therefore answer important questions about whether some of the well-documented cardio- and renal- protective effects of estrogen may occur via down-regulation of AT1 receptors in the adrenal and kidney, two key effector organs of the RAS.
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