AT1 Receptors in Renal Microvascular Physiology

AT1 受体在肾微血管生理学中的作用

• 批准号: 7069520
• 负责人: Lisa M. Harrison-Bernard
• 金额: $ 21.8万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069520
• 关键词: ACE inhibitors; angiotensin II; angiotensin receptor; dietary sodium; hemodynamics; kidney circulation; kidney function; laboratory mouse; microcirculation; nitric oxide; nitric oxide synthase; nutrition related tag; protein isoforms; protein localization

DESCRIPTION (provided by applicant): Angiotensin (Ang) II has powerful effects on the kidney which are mediated primarily by the AT1 receptor. There are 2 unique AT1 receptor subtypes in rodents, AT1A and AT1B, which cannot be distinguished using pharmacological antagonists. Accordingly, the long term goal of this project is to determine the contribution of AT1A and AT1B receptors in mediating AnglI actions on renal microvascular function. The overall hypothesis to be tested is that the distribution of the AT1 A and AT1 B receptors along the renal microvasculature is not uniform; afferent arterioles have both AT1A and AT1 B subtypes, whereas effereni arterioles have only the AT1A receptor subtype. Therefore, the compensatory functions of the AT1A and AT1B receptors are restricted to the preglomerular vasculature. The hypothesis will be tested in the following specific aims: 1) To map the distribution of the ATIA and ATIB receptors on the pre- and postglomerular vasculature; 2) To elucidate the mechanism of calcium signaling evoked by activation of afferent and efferent arteriolar AT1A and AT1B receptors; 3) To determine the changes in microvascular AT1A and AT1B receptor expression and function in response to alterations in circulating Angli levels; and 4) To examine the functional consequences of renal microvascular AT1 receptor absence on the activity of counterregulatory vasodilatory actions of nitric oxide (NO) derived from neuronal (nNOS) and/or endothelial (eNOS) nitric oxide synthases. Mice with targeted disruption of AT1A and/or AT1B receptors will be studied to discern the functions of the AT1 receptor subtypes. Angli responses will be determined by direct visualization of preglomerular (arcuate, interlobular artery, afferent arteriole) and postglomerular (efferent arteriole, descending vasa recta) vasculature using the mouse in vitro blood perfused juxtamedullary nephron technique. Regulation of AT1 receptor subtype microvascular function and mRNA and protein expression/localization will be determined during chronically altered Angil levels mediated by varied salt intake, angiotensin converting enzyme inhibition, and Angil infusion. The interaction of AT1 receptors and NO derived from nNOS and eNOS on renal microvascular function will be evaluated by pharmacological approaches. The results of these studies will delineate the complex, overlapping, and distinct functions of AT1 receptors in controlling renal microvascular hemodvnamics.

描述（由申请人提供）：血管紧张素（Ang）II对肾脏具有强大的作用，其主要由AT1受体介导。 啮齿动物中有 2 种独特的 AT1 受体亚型：AT1A 和 AT1B，无法使用药理学拮抗剂区分。 因此，该项目的长期目标是确定AT1A和AT1B受体在介导AnglI对肾微血管功能的作用中的贡献。 要测试的总体假设是 AT1 A 和 AT1 B 受体沿肾微血管的分布不均匀；传入小动脉具有 AT1A 和 AT1 B 两种亚型，而传出小动脉仅具有 AT1A 受体亚型。 因此，AT1A和AT1B受体的代偿功能仅限于肾小球前血管系统。 该假设将在以下具体目标中得到检验： 1）绘制 ATIA 和 ATIB 受体在肾小球前和肾小球后血管系统上的分布图； 2) 阐明传入和传出小动脉AT1A和AT1B受体激活引起的钙信号传导机制； 3) 确定微血管 AT1A 和 AT1B 受体表达和功能因循环 Angli 水平变化而发生的变化； 4) 检查肾微血管 AT1 受体缺失对源自神经元 (nNOS) 和/或内皮 (eNOS) 一氧化氮合酶的一氧化氮 (NO) 反调节血管舒张作用活性的功能影响。 将研究靶向破坏 AT1A 和/或 AT1B 受体的小鼠，以辨别 AT1 受体亚型的功能。 Angli 反应将通过使用小鼠体外血液灌注近髓肾单位技术直接观察肾小球前（弓状、小叶间动脉、传入小动脉）和肾小球后（传出小动脉、降血管直肠）脉管系统来确定。 AT1 受体亚型微血管功能以及 mRNA 和蛋白质表达/定位的调节将在由不同盐摄入、血管紧张素转换酶抑制和 Angil 输注介导的长期改变的 Angil 水平过程中确定。 AT1 受体与 nNOS 和 eNOS 衍生的 NO 对肾微血管功能的相互作用将通过药理学方法进行评估。 这些研究的结果将描述 AT1 受体在控制肾微血管血液动力学中复杂、重叠和独特的功能。