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对主要由AT1受体介导的肾脏具有强大的作用。 啮齿动物，AT1A和AT1B中有2种独特的AT1受体亚型，无法使用药理学拮抗剂来区分它们。 因此，该项目的长期目标是确定AT1A和AT1B受体在中介Angli作用对肾脏微血管功能的贡献。 要测试的总体假设是，沿肾小管系统的AT1 A和AT1 B受体的分布并不均匀。传入小动脉具有AT1A和AT1 B亚型，而Effereni动脉仅具有AT1A受体亚型。 因此，AT1A和AT1B受体的补偿功能仅限于肿瘤前脉管系统。 该假设将在以下特定目的中进行检验：1）绘制在肿瘤前和盆腔后脉管系统上的ATIA和ATIB受体的分布； 2）阐明通过激活传入和传染性小动脉AT1A和AT1B受体引起的钙信号传导机制； 3）确定微血管AT1A和AT1B受体表达的变化以及响应于循环的Angli水平的改变； 4）检查肾脏微血管AT1受体缺失对源自神经元（NNOS）和/或内皮（ENOS）一氧化氮合酶的反调节血管舒张作用的活性的功能后果。 将研究具有AT1A和/或AT1B受体靶向破坏的小鼠，以辨别AT1受体亚型的功能。 Angli反应将通过直接可视化前胶质细胞（弧形，叶间动脉，传入小动脉）和使用小鼠体内体外血液灌注浓度的浓含量的nephron技术来确定。 在慢性变化的盐摄入量，血管紧张素转化酶抑制和血管静脉输注的过程中，将确定AT​​1受体亚型微血管功能以及mRNA和蛋白质表达/定位的调节。 AT1受体的相互作用以及NNOS和eNOS在肾脏微血管功能上的相互作用将通过药理学方法评估。 这些研究的结果将描述AT1受体在控制肾脏微血管血液流动性方面的复合，重叠和不同功能。