Estrogen, ACE2 and Salt-Sensitivity

描述（由申请人提供）：雌激素保护女性免受心血管疾病的作用仍然是一个复杂而有争议的领域。在这方面，我们开发了基因mRen(2)。在高血压的发展中表现出明显的性别差异。子宫内膜切除术(2)。与完整的mRen相比，Lewis基因大鼠的血压会迅速而深刻地升高(2)。Lewis或卵巢切除（OVX）的血压正常的Lewis大鼠（bbb50 mmHg）消除了血压的性别差异。通过低剂量雌激素（17b -雌二醇）替代或阻断肾素-血管紧张素-醛固酮系统（RAAS）使血压正常化。卵巢切除术对mRen血压升高的显著影响(2)。Lewis菌株与自发性高血压大鼠（SHR）卵巢切除术后对血压没有影响形成对比。因此，mRen(2)。Lewis菌株提供了一个独特而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，雌激素的丧失导致血压升高，这是由于RAAS中升压因子[ACE-Ang II]和降压因子[ACE2-Ang-(1-7)]的平衡失调。此外，这种不平衡还会影响其他系统，包括内皮素（ET）、活性氧（ROS）和肾一氧化氮（NOS）系统，这些系统可能是钠摄入量增加导致血压升高和肾损伤的基础。总体目标是：1)建立mRen血压改变的机制(2)。Lewis雌性大鼠专注于循环和肾内RAAS的升压和降压成分的调节；2)雌激素的减少消除了钠摄入量增加对RAAS的抑制作用；3)确定加压系统ET和ROS在雌激素耗竭后高血压发生和维持中的作用程度；4)建立降肾通路NOS对雌激素缺失mRen中高血压和盐敏感性发展的影响(2)。刘易斯的压力。

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.