Actions of Angiotensin II Along the Nephron to Regulate Blood Pressure

血管紧张素 II 沿着肾单位调节血压的作用

基本信息

批准号：
9044767
负责人：
Susan Bailey Gurley
金额：
$ 34.63万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044767
关键词：
Affect Angiotensin II Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Angiotensins Animals Blood Circulation Blood Pressure Boxing Cardiovascular system Cells Chronic Chronic Kidney Failure Control Locus Distal Diuretics Epithelial Epithelium Excretory function Gene Targeting Generations Genes Genetic Goals Health Heart failure Homeostasis Hypertension Hypotension Infusion procedures Kidney Kidney Failure Link Liquid substance Mediator of activation protein Mus Natriuresis Nephrons Organ Oxidative Stress Pathway interactions Patients Proximal Kidney Tubules Regulation Renal function Renin-Angiotensin System Signal Pathway Signal Transduction Site Sodium Stroke Techniques Testing Transcriptional Regulation Tubular formation base biological adaptation to stress blood pressure reduction blood pressure regulation cellular targeting clinically significant hypertension treatment mouse model novel paracrine pressure receptor response response to injury urinary

项目摘要

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.

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；肾素 - 血管紧张素系统（RAS）的阻断降低了大多数高血压患者的血压。 RAS的临床意义是由RAS封锁（血管紧张素转化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实质性益处的体现。我们已经在小鼠中使用了基因靶向来鉴定肾脏中RA的细胞靶标，以控制血压。我们最近的研究确定肾近端小管作为关键部位 RAS调节完整动物的血压。仅来自肾近端小管缺乏AT1受体的小鼠的血压较低，与保护血管紧张素II诱导的高血压和尿中钠处理的改变有关。现在，我们假设肾脏近端小管中的AT1受体设置了肾内Ras的水平，然后可以在肾单位的不同段中发挥作用，以调节血压和液体稳态。该项目的总体目标是在肾脏中建立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的来实现血压：确定近端小管AT1受体如何直接在PT内调节上皮功能（1），沿着nephron沿着PT和（2）。我们将检查特定的途径，例如肾脏内RA，氧化应激和与肾近端小管中血管紧张素信号传导相关的转运蛋白调节。