Renal AT2 Receptors in Hypertension

描述（由申请人提供）：肾素-血管紧张素系统（RAS）是一个激素级联，对血压、体液和电解质平衡以及肾功能的调节具有重要的关键作用。血管紧张素II （angii）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的作用是由AT1受体介导的，包括细胞增殖、血管收缩和抗尿。我们对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，而Ang II对AT1受体的作用相反。AT2受体在体液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，而Ang II的七肽衍生物，去天冬氨酸-Ang II （Ang III）是首选的激动剂。主要研究者也有初步数据强烈提示多巴胺D1受体刺激诱导肾近端小管细胞顶膜AT2受体表达增加，抑制AT2受体可消除D1受体诱导的尿钠。本项目将深入探讨AT2受体诱导尿钠的位点和机制。该项目将重点关注两个具体假设：(1)肾近端小管中的AT2受体是对Ang III、AT1受体阻断、D1受体激活和肾灌注压力升高的钠尿反应的关键介质；(2) AT2受体介导的钠尿在幼年高血压前期自发性高血压大鼠（SHR）中存在缺陷。该项目将结合最先进的体内和细胞及分子技术来阐明AT2受体在高血压患者钠排泄中的作用。这些研究将有助于阐明人类原发性高血压的病理生理学，这是一种影响西方世界四分之一成年人的疾病。

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.