Angiotensin receptor genes and blood pressure regulation

血管紧张素受体基因与血压调节

• 批准号: 7117836
• 负责人: THOMAS M COFFMAN
• 金额: $ 29.22万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7117836
• 关键词: angiotensin II; angiotensin receptor; biological signal transduction; blood pressure; dietary sodium; echocardiography; gene deletion mutation; genetic regulation; genetically modified animals; homeostasis; hypertension; kidney function; kidney transplantation; laboratory mouse; molecular pathology; muscle cells; protein structure function; renal tubule; renin angiotensin system; urinalysis; vascular resistance; vascular smooth muscle

DESCRIPTION (provided by applicant): The actions of the renin-angiotensin system (RAS) to control blood pressure are primarily mediated by type 1 (AT1) angiotensin receptors. The key role of AT1 receptors in blood pressure homeostasis is highlighted by the phenotype of mice lacking the AT1A receptor, the major murine AT1 receptor isoform. We have previously shown that these animals have markedly reduced blood pressures and profound sodium sensitivity. As AT1 receptors are ubiquitously expressed and have myriad actions in every major organ system, it has been difficult in the intact animal to precisely dissect and quantify the contribution of AT1 receptors in individual tissue compartments to the regulation of blood pressure. In work done during the previous funding period using a cross-transplantation strategy, we showed that AT1A receptors in the kidney have unique, aldosterone-independent actions to determine the normal level of blood pressure. We hypothesize that these critical regulatory actions are mediated by AT1 receptors in specific renal epithelial lineages where they directly modulate sodium reabsorption. Our previous studies also showed that AT1A receptors outside the kidney make definitive and non-redundant contributions to blood pressure homeostasis and that the magnitude of this effect is similar to that of intra-renal AT1A receptors. We posit that this extra-renal control of blood pressure is primarily accomplished through regulation of vascular resistance by AT1 receptors in vascular smooth muscle cells. To test these hypotheses, we will develop novel mouse lines with deletion of AT1 receptors in specific nephron segments and in vascular smooth muscle cells. By determining the physiological consequences of interrupting AT1 receptor signaling in these circumscribed tissue compartments, we will identify the key cell lineages used by the RAS as a mechanism to control blood pressure. These studies have 3 specific aims: (1) To identify renal epithelia/cell lineages that are critical for the regulation of blood pressure by AT1 receptors, (2) To determine whether the actions of AT1 receptors in vascular smooth muscle cells are a major mechanism for chronic blood pressure control, (3) To define the role of renal AT1 receptors in the pathogenesis of hypertension.

描述（由申请人提供）：肾素-血管紧张素系统（RAS）控制血压的作用主要由1型（AT1）血管紧张素受体介导。缺乏 AT1A 受体（主要的鼠 AT1 受体亚型）的小鼠的表型凸显了 AT1 受体在血压稳态中的关键作用。我们之前已经证明，这些动物的血压显着降低，并且对钠高度敏感。由于 AT1 受体在每个主要器官系统中普遍表达并具有多种作用，因此很难在完整的动物中精确剖析和量化单个组织区室中 AT1 受体对血压调节的贡献。在上一个资助期间使用交叉移植策略完成的工作中，我们表明肾脏中的 AT1A 受体具有独特的、独立于醛固酮的作用来确定正常血压水平。我们假设这些关键的调节作用是由特定肾上皮谱系中的 AT1 受体介导的，它们直接调节钠的重吸收。我们之前的研究还表明，肾外的 AT1A 受体对血压稳态做出明确且非多余的贡献，并且这种作用的程度与肾内 AT1A 受体相似。我们假设这种肾外血压控制主要是通过血管平滑肌细胞中 AT1 受体调节血管阻力来实现的。为了检验这些假设，我们将开发新的小鼠品系，删除特定肾单位节段和血管平滑肌细胞中的 AT1 受体。通过确定中断这些有限组织区室中 AT1 受体信号传导的生理后果，我们将确定 RAS 用作控制血压机制的关键细胞谱系。这些研究有 3 个具体目标：(1) 确定对 AT1 受体调节血压至关重要的肾上皮/细胞谱系，(2) 确定血管平滑肌细胞中 AT1 受体的作用是否是慢性血压控制的主要机制，(3) 明确肾 AT1 受体在高血压发病机制中的作用。