Estrogen, ACE2 and Salt-Sensitivity

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DESCRIPTION (provided by applicant): The role of estrogen to protect women from cardiovascular disease remains a complicated and controversial area. In this regard, we have developed the congenic mRen (2). Lewis rat that present a marked gender difference in the development of the hypertension. Ovariectomy in the mRen (2). Lewis congenic rat produces a rapid and profound increase in blood pressure in comparison to intact mRen (2). Lewis or the ovariectomized (OVX) normotensive Lewis rats (>50 mmHg) abolishing the gender difference in blood pressure. Blood pressure was normalized by either low dose estrogen (17B-estradiol) replacement or blockade of the renin-angiotensin-aldosterone system (RAAS). The significant effect of ovariectomy to increase blood pressure in the mRen (2). Lewis strain contrasts with the lack of an effect on blood pressure following ovariectomy in the spontaneously hypertensive rat (SHR). Thus, the mRen (2). Lewis strain presents a unique and relevant model to investigate the role of estrogen in the regulation of blood pressure. The overall hypothesis of the present application is that the loss of estrogen results in elevated blood pressure due to dysregulation in the balance of both pressor [ACE-Ang II] and depressor [ACE2-Ang- (1-7)] components of the RAAS. Furthermore, this imbalance influences additional systems including the endothelin (ET), reactive oxygen (ROS) and renal nitric oxide (NOS) systems that may underlie the exaggerated blood pressure response and renal injury to increased sodium intake. The overall aims will: 1) Establish the mechanisms for alteration of blood pressure in the mRen (2). Lewis female rats focusing on the regulation of both pressor and depressor components of the circulating and intrarenal RAAS; 2) Demonstrate that loss of estrogen abrogates the inhibitory influence on the RAAS during an increase in sodium intake; 3) Determine the extent that the pressor systems ET and ROS contribute to the development and maintenance of hypertension following estrogen depletion; 4) Establish the influence of the renal depressor pathway NOS to the development of hypertension and salt-sensitivity in the estrogen depleted mRen(2).Lewis strain.