Angiotensin receptor genes and blood pressure regulation

描述(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。AT1受体在血压动态平衡中的关键作用被缺乏AT1a受体的小鼠的表型所强调，AT1a受体是小鼠AT1受体的主要亚型。我们之前已经证明，这些动物显著降低了血压，并对钠有很强的敏感性。由于AT1受体在各个主要器官系统中普遍表达，并具有多种作用，因此在完整的动物中，很难准确地解剖和量化单个组织中的AT1受体对血压调节的作用。在之前的资助期间使用交叉移植策略所做的工作中，我们证明了肾脏中的AT1a受体具有独特的、不依赖于醛固酮的作用来确定正常的血压水平。我们假设，这些关键的调节作用是由特定肾上皮细胞中的AT1受体介导的，在那里，AT1受体直接调节钠的重吸收。我们以前的研究也表明，肾脏外的AT1a受体对血压稳态有明确和非多余的贡献，这种作用的幅度类似于肾内的AT1a受体。我们推测，肾外对血压的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完成的。为了验证这些假设，我们将开发在特定肾单位节段和血管平滑肌细胞中缺失AT1受体的新型小鼠株系。通过确定在这些受限的组织间隔中中断AT1受体信号的生理后果，我们将确定RAS使用的关键细胞系作为控制血压的机制。这些研究有3个具体目的：(1)确定AT1受体对血压调节至关重要的肾上皮/细胞系；(2)确定血管平滑肌细胞AT1受体的作用是否是慢性血压控制的主要机制；(3)确定肾脏AT1受体在高血压发病机制中的作用。

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.