Natriuretic mechanisms of AT2 receptors

描述（由申请方提供）：肾素-血管紧张素系统（RAS）是一种激素级联反应，对血压、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稳态中的作用尚不清楚。主要研究者的初步数据表明，AT 2受体介导尿钠排泄，并且Ang II的半肽衍生物去乙酰-Ang II（Ang III）是首选激动剂。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。该项目将集中在两个特定的假设：（1）AT 2受体是对Ang III，D1受体激活和肾灌注压增加的利钠反应的关键介导剂;和（2）对Ang II和D1样受体激活的利钠反应需要AT 2受体募集到肾近端小管细胞的顶端质膜，并由缓激肽，一氧化氮和环GMP介导。该项目将应用最先进的体内细胞和分子技术相结合，以阐明AT 2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，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 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.