Natriuretic mechanisms of AT2 receptors

AT2受体的利尿钠排泄机制

基本信息

批准号：
7894698
负责人：
ROBERT MUNSON CAREY
金额：
$ 45.21万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7894698
关键词：
AGTR2 gene ATP phosphohydrolase Adult Affect Agonist Angiotensin II Angiotensin III Apical Arts Blood Pressure Blood Vessels Bradykinin Cell Proliferation Cell membrane Cells Cessation of life Cyclic GMP Data Disease Dopamine D1 Receptor Electrolyte Balance Electrolytes Endosomes Enzymes Essential Hypertension Excretory function Fenoldopam Functional disorder Goals Growth Heart Homeostasis Hormonal Hypersensitivity Hypertension Kidney Knockout Mice Laboratories Liquid substance Mediating Mediator of activation protein Membrane Molecular Molecular Target Natriuresis Nitric Oxide Peptides Perfusion Plasma Play Population Principal Investigator Proximal Kidney Tubules Rattus Receptor Activation Receptor Inhibition Recruitment Activity Recycling Regulation Renal function Renin-Angiotensin System Risk Factors Role Signal Pathway Site Sodium Sodium Chloride Stimulation of Cell Proliferation Stimulus Techniques Testing Vasodilation Water Western World alanine aminopeptidase apical membrane basolateral membrane blood pressure regulation 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 homeostasis is unknown. The Principal Investigator has pilot data demonstrating that the AT2 receptor mediates natriuresis and that the haptapeptide 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) the AT2 receptor is a key mediator of the natriuretic response to Ang III, D1 receptor activation and increased renal perfusion pressure; and (2) natriuretic responses to Ang II and D1 like receptor activation require AT2 receptor recruitment to the apical plasma membrane of renal proximal tubule cells and are mediated by bradykinin, nitric oxide and cyclic GMP. 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. These studies will help clarify the pathophysiology of 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）是对调节血压，液体和电解质平衡和肾功能的荷尔蒙级联。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，血管收缩和抗阳离子。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与AT AT AT 1受体的影响相反的血管舒张。 AT2受体在液体和电解质稳态中的作用尚不清楚。主要研究者的试验数据表明，AT2受体介导了Natriuresis，并且Ang II（des-aspartyl-ang ang ii）（ANG III）的触觉肽衍生物是首选的激动剂。首席研究者还拥有初步数据，表明多巴胺D1受体刺激会诱导肾脏近端小管细胞顶膜AT2受体表达增加，并且抑制AT2受体的人消除了D1受体诱导的NATRIURISIS。该项目将深入探索AT2受体诱导的Natriuresis的位点和机制。该项目将重点放在两个特定的假设上：（1）AT2受体是对Ang III，D1受体激活和肾脏灌注压力增加的纳地尿症反应的关键介体；（2）对ANG II和D1的亚催化剂反应像受体激活需要AT2受体募集到肾近端小管细胞的顶质膜，并由头蓬金，一氧化氮和环状GMP介导。该项目将使用最新的体内和细胞和分子技术的组合来阐明AT2受体在钠排泄中的作用。这些研究将有助于阐明原发性高血压的病理生理学，这是一种影响西方世界成年人口后四分之一的疾病。公共卫生相关性西方世界人口中25％以上的高血压（高血压）是心脏和血管疾病导致早期死亡和残疾的主要危险因素。高血压需要通过肾脏保留盐和水。该应用将增加我们对肾脏肾素 - 血管紧张素系统调节盐和水排泄的机制的理解，这表明了用于治疗和预防高血压的新分子靶标。