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Renal AT2 Receptors in Hypertension

高血压中的肾 AT2 受体

基本信息

批准号：
9249632
负责人：
ROBERT MUNSON CAREY
金额：
$ 56.66万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249632
关键词：
5&apos -Nucleotidase AGTR2 gene Acute Adult Affect Agonist Angiotensin II Angiotensin III Apical Blood Pressure Blood Vessels Bradykinin Cell membrane Cells Cessation of life Chronic Cyclic AMP Cyclic GMP Defect Deltastab Dependency Disease Dopamine Essential Hypertension Excretory function Fenoldopam Functional disorder Goals Heart Human Hypertension Impairment Inbred SHR Rats Inbred WKY Rats Infusion procedures Kidney Laboratories Lead Measurement Mediating Metabolism Microtubules Molecular Na(+)-K(+)-Exchanging ATPase Natriuresis Nitric Oxide Pathogenesis Peptides Population Protein phosphatase Proximal Kidney Tubules Rattus Receptor Activation Recruitment Activity Renin Renin-Angiotensin System Risk Factors Role Signal Pathway Site Sodium Sodium Chloride Sprague-Dawley Rats System Techniques Testing Transducers Transplantation Water Western World alanine aminopeptidase cGMP production disability hypertension prevention in vivo molecular targeted therapies new therapeutic target normotensive premature prevent public health relevance receptor response saluretic

项目摘要

DESCRIPTION (provided by applicant): Angiotensin (Ang) II, the primary transducer peptide of the renin-Ang system (RAS), acts at two major receptors: type-1 (AT1R) and type-2 (AT2R). The majority of Ang II actions occur via AT1Rs, including antinatriuresis. Renal cross-transplantation studies have demonstrated that renal AT1Rs are both necessary and sufficient for the induction and sustainability of hypertension during Ang II infusion and that increased Na+ reabsorption in the renal proximal tubule (RPT) is the major determinant of this response. In contrast, the role of AT2Rs in the control of Na+ excretion and hypertension is less clearly defined. Recent studies from our laboratory have provided evidence for a major role of RPT AT2Rs in the inhibition of Na+ reabsorption. These studies have provided evidence that, instead of Ang II, des-aspartyl1-Ang II (Ang III) is the preferred AT2R agonist inducing natriuresis. Furthermore, we now have evidence for a defect in AT2R-mediated natriuresis in spontaneously hypertensive rats (SHR) that pre-dates the hypertension and is due, at least in part, to accelerated intrarenal Ang III metabolism. Overall, our results suggest that AT2R-induced natriruesis is defective and contributes to the pathogenesis of hypertension in SHR. The overall goal of this project is to elucidate the mechanisms of defective AT2R-mediated natriuresis in SHR. The project will focus on three specific aims: (1) To test the hypothesis that defective AT2R-mediated natriuresis is important in the pathogenesis of HT in SHR; (2) To test the hypothesis that impaired natriuresis in SHR is due to reduction of Ang III; and (3) To test the hypothesis that chronic AT2R activation can restore normal natriuresis and prevent HT in SHR. The project will apply a combination of state-of-the-art in vivo and cell and molecular techniques, including intrarenal Ang II and III measurements, to clarify the role of the AT2R in sodium excretion in hypertension. These studies will help define the pathophysiology of human primary hypertension, a disorder affecting one-quarter after adult population in the Western world.

描述（由申请人提供）：血管紧张素（Ang）II是肾素-Ang系统（RAS）的主要转导肽，作用于两种主要受体：1型（AT 1 R）和2型（AT 2 R）。大多数血管紧张素II的作用是通过AT 1 R发生的，包括抗白尿。肾交叉移植研究表明，肾AT 1 R是必要的和足够的诱导和维持高血压期间血管紧张素II输注和增加Na+重吸收的肾近端小管（RPT）是这种反应的主要决定因素。相比之下，AT 2 Rs在控制Na+排泄和高血压中的作用尚不清楚。我们实验室的最新研究为RPT AT 2 Rs在抑制Na+重吸收中的重要作用提供了证据。这些研究提供了证据，而不是血管紧张素II，去乙酰化-血管紧张素II（血管紧张素III）是优选的AT 2受体激动剂诱导尿钠排泄。此外，我们现在有证据表明，AT 2 R介导的尿钠排泄在自发性高血压大鼠（SHR），早于高血压，是由于，至少部分，肾内血管紧张素III代谢加速的缺陷。总之，我们的研究结果表明，AT 2 R诱导的钠分泌是有缺陷的，并有助于高血压的发病机制在SHR。该项目的总体目标是阐明自发性高血压大鼠AT 2 R介导的尿钠排泄缺陷的机制。该项目将集中于三个具体目标：（1）验证AT 2 R介导的尿钠排泄缺陷在SHR HT发病机制中的重要性的假设;（2）验证SHR尿钠排泄受损是由于Ang III减少的假设;（3）验证慢性AT 2 R激活可以恢复正常尿钠排泄并预防SHR HT的假设。该项目将应用最先进的体内细胞和分子技术，包括肾内血管紧张素II和III的测量相结合，以阐明AT 2 R在高血压钠排泄中的作用。这些研究将有助于确定人类原发性高血压的病理生理学，在西方世界，原发性高血压是一种影响四分之一成年人的疾病。