Renal AT2 Receptors in Hypertension

描述（由申请人提供）：血管紧张素系统（RAS）是一种激素级联反应，对于调节血压、液体和电解质平衡以及肾功能至关重要。血管紧张素II（Ang II）是RAS的主要效应肽，作用于两种主要受体AT 1和AT 2。绝大多数血管紧张素II的行动是由AT 1受体介导的，包括细胞增殖，血管收缩和抗尿。关于AT 2受体的功能知之甚少。最近的研究表明，AT 2受体抑制细胞生长并诱导血管舒张，对抗Ang II对AT 1受体的作用。AT 2受体在体液和电解质平衡中的作用尚不清楚。主要研究者的初步数据表明，AT 2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，去乙酰化-Ang II（Ang III）是优选的激动剂。主要研究者的初步数据也强烈表明，多巴胺D1受体刺激诱导肾近端小管细胞顶膜AT 2受体表达增加，抑制AT 2受体可消除D1受体诱导的尿钠排泄。本项目将深入探讨AT 2受体介导的钠尿排泄的部位和机制。本项目将集中于两个特定的假设：（1）肾近端小管中的AT 2受体是对Ang III的利钠反应、AT 1受体阻断、D1受体激活和肾灌注压升高的关键介质;（2）在年轻的高血压前期自发性高血压大鼠（SHR）中，AT 2受体介导的利钠作用是有缺陷的。该项目将应用最先进的体内和细胞及分子技术相结合，以阐明AT 2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，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。 公共卫生相关性：高血压（高血压），目前在超过25%的人口的西方世界，是一个主要的危险因素，心脏和血管疾病，导致过早死亡和残疾。高血压的发生需要肾脏保留盐和水。这一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，为高血压的治疗和预防提供新的分子靶点。

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.