Renal AT2 Receptors in Hypertension

高血压中的肾 AT2 受体

基本信息

批准号：
7887245
负责人：
ROBERT MUNSON CAREY
金额：
$ 44.88万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7887245
关键词：
AGTR2 gene Adult Affect Age Agonist Angiotensin II Angiotensin III Animals Apical Arts Blood Pressure Blood Vessels Blood capillaries Cell Proliferation Cell membrane Cells Cessation of life Data Defect Development Disease Dopamine Dopamine D1 Receptor Electrolyte Balance Electrolytes End stage renal failure Enzymes Essential Hypertension Excretory function Exhibits Fenoldopam Functional disorder Goals Heart Heart failure Hormonal Human Hypertension Inbred SHR Rats Inbred Strain Infusion procedures Kidney Laboratories Lead Ligands Liquid substance Mediating Mediator of activation protein Modeling Molecular Molecular Target Myocardial Infarction Natriuresis Nephrons Peptides Perfusion Play Population Principal Investigator Proximal Kidney Tubules Rattus Receptor Activation Receptor Inhibition Recruitment Activity Regulation Renal function Renin-Angiotensin System Risk Risk Factors Rodent Role Site Sodium Sodium Chloride Sprague-Dawley Rats Stimulus Stroke Techniques Testing Time Transplantation Vasodilation Water Western World alanine aminopeptidase apical membrane blood pressure regulation capillary cell growth disability hypertension prevention in vivo premature pressure public health relevance receptor receptor expression response saluretic urinary vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The renin-angiotensin system (RAS) is a hormonal cascade of major critical importance to the regulation of blood pressure, fluid and electrolyte balance and kidney function. Angiotensin II (Ang II), the main effector peptide of the RAS, acts at two major receptors, AT1 and AT2. The vast majority of Ang II actions are mediated by the AT1 receptor, including cell proliferation, vasoconstriction and antinatriuresis. Much less is known concerning the functions of the AT2 receptor. Recent studies indicate that the AT2 receptor inhibits cell growth and induces vasodilation opposing the effects of Ang II at AT1 receptors. The role of the AT2 receptors in fluid and electrolyte homeostatsis is unknown. The Principal Investigator has preliminary data demonstrating that the AT2 receptor mediates natriuresis in normal Sprague-Dawley rats and that the heptapeptide derivative of Ang II, des-aspartyl-Ang II (Ang III), is the preferred agonist. The Principal Investigator also has preliminary data strongly suggesting that dopamine D1-receptor stimulation induces increased renal proximal tubule cell apical membrane AT2 receptor expression and that inhibition of AT2 receptors abolishes D1 receptor-induced natriuresis. This project will explore in depth the site and mechanisms of AT2 receptor-induced natriuresis. The project will focus on two specific hypotheses: (1) AT2 receptors in the renal proximal tubule are key mediators of the natriuretic responses to Ang III, AT1 receptor blockade, D1 receptor activation and increased renal perfusion pressure; and (2) AT2 receptor-mediated natriuresis is defective in young pre-hypertensive spontaneously hypertensive rats (SHR). The project will apply a combination of state-of-the-art in vivo and cell and molecular techniques to clarify the role of the AT2 receptor in sodium excretion in hypertension. These studies will help clarify the pathophysiology of human primary hypertension, a disorder affecting one-quarter after adult population in the Western world. PUBLIC HEALTH RELEVANCE: Hypertension (high blood pressure), present in over 25% of the population of the Western world, is a major risk factor for heart and blood vessel disease leading to premature death and disability. Retention of salt and water by the kidney is required for hypertension to develop. This application will increase our understanding of the mechanisms whereby the kidney renin-angiotensin system regulates salt and water excretion, suggesting new molecular targets for the treatment and prevention of hypertension.

描述（由申请人提供）：肾素-血管紧张素系统（RAS）是一种激素级联，对于血压、体液和电解质平衡以及肾功能的调节至关重要。血管紧张素 II (Ang II) 是 RAS 的主要效应肽，作用于两个主要受体 AT1 和 AT2。绝大多数 Ang II 作用是由 AT1 受体介导的，包括细胞增殖、血管收缩和抗尿钠排泄。关于 AT2 受体的功能知之甚少。最近的研究表明，AT2 受体抑制细胞生长并诱导血管舒张，对抗 Ang II 对 AT1 受体的影响。 AT2 受体在液体和电解质稳态中的作用尚不清楚。首席研究员的初步数据表明，AT2 受体介导正常 Sprague-Dawley 大鼠的尿钠排泄，并且 Ang II 的七肽衍生物，去天冬氨酰-Ang II (Ang III)，是首选激动剂。首席研究员还有初步数据强烈表明，多巴胺 D1 受体刺激会诱导肾近曲小管细胞顶膜 AT2 受体表达增加，而 AT2 受体的抑制会消除 D1 受体诱导的尿钠排泄。该项目将深入探讨AT2受体诱导尿钠排泄的位点和机制。该项目将重点关注两个具体假设：（1）肾近曲小管中的 AT2 受体是 Ang III 利尿钠反应、AT1 受体阻断、D1 受体激活和肾灌注压增加的关键介质； (2)年轻高血压前期自发性高血压大鼠(SHR)中AT2受体介导的尿钠排泄存在缺陷。该项目将应用最先进的体内、细胞和分子技术相结合，阐明 AT2 受体在高血压钠排泄中的作用。这些研究将有助于阐明人类原发性高血压的病理生理学，这种疾病影响着西方世界四分之一的成年人口。公共卫生相关性：西方世界 25% 以上的人口患有高血压，是导致过早死亡和残疾的心脏和血管疾病的主要危险因素。高血压的发生需要肾脏保留盐和水。这一应用将增进我们对肾脏肾素-血管紧张素系统调节盐和水排泄机制的理解，为治疗和预防高血压提供新的分子靶点。