Renal AT2 Receptors in Hypertension

高血压中的肾 AT2 受体

基本信息

批准号：
9460298
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/9460298
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 Dependence 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 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 recruit 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，肾素-Ang系统（RAS）的主要转导肽，作用于两种主要受体：1型（AT1R）和2型（AT2R）。 Ang II 作用通过 AT1R 发生，包括肾交叉移植研究表明，肾 AT1R 对于 Ang 期间高血压的诱导和持续是必要且充分的。 II 输注和肾近曲小管 (RPT) 中 Na+ 重吸收的增加是这种反应的主要决定因素，相反，我们实验室最近的研究还不太明确 AT2R 在控制 Na+ 排泄和高血压中的作用。 RPT AT2R 在抑制 Na+ 重吸收中发挥重要作用的证据这些研究提供的证据表明，des-aspartyl1-Ang II (Ang III) 是首选。此外，我们现在有证据表明自发性高血压大鼠 (SHR) 中 AT2R 介导的尿钠缺陷早于高血压，并且至少部分归因于肾内 Ang III 代谢加速。我们的结果表明，AT2R 诱导的尿钠排泄存在缺陷，并导致 SHR 高血压的发病机制。该项目的总体目标是阐明缺陷的机制。该项目将重点关注三个具体目标：(1) 检验 AT2R 介导的尿钠排泄缺陷在 SHR HT 发病机制中发挥重要作用的假设；(2) 检验 SHR 中的钠排泄受损的假设。 SHR 是由于 Ang III 的减少；以及 (3) 检验慢性 AT2R 激活可以恢复正常尿钠排泄并预防 SHR 中的 HT 的假设。最先进的体内、细胞和分子技术，包括肾内 Ang II 和 III 测量，以阐明 AT2R 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（一种疾病）的病理生理学。影响西方世界四分之一的成年人口。