Natriuretic mechanisms of AT2 receptors

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受体介导尿钠，而Ang II的半肽衍生物，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受体刺激可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。该项目将侧重于两个特定的假设：(1)AT2受体是Ang III， D1受体激活和肾灌注压力增加的利钠反应的关键介质；(2)对Ang II和D1样受体激活的利钠反应需要AT2受体募集到肾近端小管细胞的顶质膜，并由缓激肽、一氧化氮和环GMP介导。该项目将结合最先进的体内、细胞和分子技术来阐明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 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.