Actions of Angiotensin II Along the Nephron to Regulate Blood Pressure

描述(申请人提供)：高血压在美国影响着6000多万人，尽管其原因多种多样；阻断肾素-血管紧张素系统(RAS)可以降低大多数高血压患者的血压。RAS阻滞剂(血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂)对整体心血管和肾脏健康的巨大益处证明了RAS的临床意义。我们已经在小鼠身上使用了基因打靶来确定肾脏中RAS的细胞靶点来控制血压。我们最近的研究发现，肾脏近端小管是 RAS调节完好动物的血压。仅从肾近端小管缺乏AT1受体的小鼠血压较低，这与防止血管紧张素II诱导的高血压和尿钠处理的变化有关。我们现在假设，肾近端小管中的AT1受体决定了肾内RAS的水平，然后RAS可以在肾单位的不同部分发挥作用，调节血压和液体动态平衡。这个项目的总体目标是建立肾脏中血管紧张素受体的能力。 近端小管调节血压，我们建议通过以下特定目标来实现：确定近端小管AT1受体如何调节上皮功能(1)直接在甲状旁腺内和(2)在远端，沿肾单位。我们将研究特定的途径，如肾内RAS，氧化应激，以及与肾近端小管血管紧张素信号相关的转运体调节。

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.