Actions of Angiotensin II Along the Nephron to Regulate Blood Pressure

描述（由申请人提供）：高血压影响美国超过6000万人，尽管其原因多种多样;阻断肾素-血管紧张素系统（RAS）可降低大多数高血压患者的血压。RAS阻断剂（血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂）对总体心血管和肾脏健康的实质性获益证明了RAS的临床意义。我们已经在小鼠中使用基因靶向来确定肾脏中RAS的细胞靶点以控制血压。我们最近的研究已经确定肾近端小管是一个关键的网站， RAS调节完整动物的血压。仅肾近端小管缺乏AT 1受体的小鼠血压较低，与血管紧张素II诱导的高血压和尿钠处理的改变有关。我们现在假设，肾近端小管中的AT 1受体设置肾内RAS的水平，然后可以在肾单位的不同部分发挥作用，以调节血压和液体稳态。本项目的总体目标是建立肾血管紧张素受体的能力， 近端小管调节血压，我们建议通过以下具体目标来实现：确定近端小管AT 1受体如何调节上皮功能（1）直接在PT内和（2）远端，沿着肾单位。我们将研究特定的途径，如肾内RAS，氧化应激和转运调控相关的血管紧张素信号在肾近曲小管。

DESCRIPTION (provided by applicant): Hypertension affects more than 60 million people in the US and despite its diverse causes; blockade of the renin-angiotensin system (RAS) lowers blood pressure in the majority of hypertensive patients. The clinical significance of the RAS is exemplified by the substantial benefit of RAS blockade (angiotensin converting enzyme inhibitors or angiotensin receptor blockers) on overall cardiovascular and renal health. We have used gene-targeting in mice to identify the cellular targets of the RAS in the kidney to control blood pressure. Our recent studies have identified the renal proximal tubule as a critical site for RAS to regulate blood pressure in the intact animal. Mice lacking AT1 receptors only from renal proximal tubule had lower blood pressures, associated with protection against angiotensin II-induced hypertension and alterations in urinary sodium handling. We now hypothesize that AT1 receptors in the renal proximal tubule set the level of the intrarenal RAS which can then exert effects in different segments of the nephron to regulate blood pressure and fluid homeostasis. The overall goal of this project is to establish the capacity of angiotensin receptors in the renal proximal tubule to regulate blood pressure, which we propose to accomplish through the following specific aims: To determine how proximal tubule AT1 receptors regulate epithelial function (1) directly within the PT and (2) distally, along the nephron. We will examine specific pathways such as intra- renal RAS, oxidative stress, and transporter regulation related to angiotensin signaling in the renal proximal tubule.