Estrogen, ACE2 and Salt-Sensitivity

说明(申请人提供)：雌激素保护女性心血管疾病的作用仍然是一个复杂和有争议的领域。在这方面，我们发展了同源MREN(2)。Lewis大鼠在高血压的发生发展过程中呈现明显的性别差异。卵巢切除在MREN(2)。与完整的MREN相比，Lewis同源基因大鼠的血压迅速而显著地升高(2)。Lewis或去卵巢(OVX)正常血压的Lewis大鼠(&gt；50 mm Hg)消除了血压的性别差异。血压通过小剂量雌激素(17B-雌二醇)替代或阻断肾素-血管紧张素-醛固酮系统(RAAS)而恢复正常。卵巢摘除对MREN血压升高的显著作用(2)。Lewis品系与自发性高血压大鼠(SHR)卵巢切除后对血压缺乏影响形成对比。因此，MREN(2)。Lewis品系提供了一个独特和相关的模型来研究雌激素在血压调节中的作用。目前应用的总体假设是，雌激素的丢失导致血压升高，这是由于RAAS的升压[ACE-Ang II]和降压[ACE2-Ang-(1-7)]的平衡失调所致。此外，这种失衡会影响额外的系统，包括内皮素(ET)、活性氧(ROS)和肾脏一氧化氮(NOS)系统，这些系统可能是由于钠摄入量增加而导致的过度血压反应和肾脏损伤的基础。总体目标是：1)建立MREN中血压变化的机制(2)。刘易斯雌性大鼠专注于调节循环和肾内RAAS的升压和降压成分；2)证明雌激素的丢失可以消除在钠摄入量增加时对RAAS的抑制影响；3)确定升压系统ET和ROS在雌激素耗竭后对高血压的发展和维持的贡献程度；4)建立肾脏降压通路NOS对雌激素耗竭的MREN(2)中高血压和盐敏感性发展的影响。

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.