Angiotensin receptor genes and blood pressure regulation

血管紧张素受体基因与血压调节

• 批准号: 6944953
• 负责人: THOMAS M COFFMAN
• 金额: $ 29.92万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6944953
• 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（AT 1）血管紧张素受体介导。AT 1受体在血压稳态中的关键作用通过缺乏AT 1A受体（主要的鼠AT 1受体同种型）的小鼠的表型而突出。我们以前已经证明，这些动物有显着降低血压和深刻的钠敏感性。由于AT 1受体在每个主要器官系统中普遍表达并具有无数的作用，因此在完整的动物中很难精确地解剖和量化单个组织隔室中AT 1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所做的工作中，我们发现肾脏中的AT 1A受体具有独特的，不依赖于醛固酮的作用，以确定血压的正常水平。我们假设这些关键的调节作用是由特定的肾上皮细胞系中的AT 1受体介导的，它们直接调节钠的重吸收。我们以前的研究还表明，肾脏外的AT 1A受体对血压稳态有明确的和非冗余的贡献，这种作用的大小与肾内AT 1A受体相似。我们认为，这种肾外血压控制主要是通过血管平滑肌细胞中的AT 1受体调节血管阻力来实现的。为了验证这些假设，我们将开发新的小鼠品系，在特定的肾单位节段和血管平滑肌细胞中缺失AT 1受体。通过确定中断AT 1受体信号传导在这些限定的组织隔室中的生理后果，我们将确定RAS作为控制血压的机制所使用的关键细胞谱系。这些研究有3个具体的目的：（1）确定肾上皮细胞/细胞谱系是至关重要的血压调节的AT 1受体，（2）确定血管平滑肌细胞中的AT 1受体的行动是否是一个主要的机制，慢性血压控制，（3）确定肾AT 1受体在高血压的发病机制中的作用。