RENAL AT1A RECEPTORS AND REGULATION OF BLOOD PRESSURE

钠敏感性高血压是一种常见的临床疾病。虽然钠 敏感性是一种遗传特征，其在人类中的遗传原因是 晦涩难懂。肾素-血管紧张素系统是一个重要的生理 血压和钠稳态的调节剂。然而，一个角色 钠敏感性发病机制中的肾素-血管紧张素系统 并没有被具体描述。这些研究的目的是 确定AT 1A受体基因在调节 定义钠敏感性的生理反应。在这些研究中， 我们将检验AT 1A受体基因座（Agtr 1A）， 特别是肾脏中Agtr 1A的表达，是中枢神经系统的重要组成部分。 在调节血压和钠稳态中的重要性。我们将 使用小鼠模型来实现这一点，其中Agtr 1A基因的表达 在胚胎中利用同源重组进行了特异性改变， 干细胞我们的第一个具体目标是检查相对 AT 1A受体对钠和血压的作用 通过检查缺乏AT 1A受体的小鼠对 盐摄入量和容量状态的变化，DOCA盐，以及药理学 操纵其他血管紧张素受体和血管活性系统。我们 第二个具体目的是评估肾AT 1A受体的作用。两 将采用互补办法。首先，我们将进行肾脏检查 Agtr 1A（-/-）小鼠之间的交叉移植实验， AT 1A受体和野生型对照。 第二，使用一种新的基因 靶向策略，我们将开发转基因小鼠品系， 肾特异性启动子控制下的AT 1A受体。的 将转基因动物与Agtr 1A（-/-）系杂交以获得 仅在近端肾小管上皮细胞上表达AT 1A受体的小鼠 细胞通过这种方式，我们可以测试肾小管AT 1A受体的容量 以刺激体内钠重吸收。将动物暴露至 一系列研究来确定肾脏和 非肾AT 1A受体与生理参数的关系 钠敏感表型 这些实验应该能让我们 分别评估肾脏与全身AT 1A的贡献 受体循环稳态的特异性，尚未被 可能以前。

Sodium sensitive hypertension is a common clinical disorder. While sodium sensitivity is an inherited trait, its genetic causes in humans are obscure. The renin-angiotensin system is a critical physiological regulator of blood pressure and sodium homeostasis. However, a role for the renin-angiotensin system in the pathogenesis of sodium sensitivity has not been specifically delineated. The aim of these studies is to determine the role of the AT1A receptor gene in modulating the physiological responses that define sodium sensitivity. In these studies, we will test the hypothesis that the AT1A receptor gene locus (Agtr1A ), and in particular Agtr1A expression in the kidney, is of central importance in regulating blood pressure and sodium homeostasis. We will accomplish this using mouse models in which expression of the Agtr1A gene has been specifically altered using homologous recombination in embryonic stem cells. Our first specific aim is to examine the relative contribution of the AT1A receptor to sodium and blood pressure homeostasis by examining the response of mice lacking AT1A receptors to changes in salt intake and volume status, DOCA salt, and by pharmacologic manipulation of other angiotensin receptors and vasoactive systems. Our second specific aim is to assess the role of renal AT1A receptors. Two complimentary approaches will be used. First, we will perform renal cross-transplantation experiments between Agtr1A (-/-) mice that lack AT1A receptors and wild type controls. Second, using a novel gene targeting strategy, we will develop lines of transgenic mice that express AT1A receptors under the control of kidney specific promoters. The transgenic animals will be crossed with the Agtr1A (-/-)line to obtain mice that express AT1A receptors only on proximal tubular epithelial cells. In this way, we can test the capacity of tubular AT1A receptors to stimulate sodium reabsorption in vivo. The animals will be exposed to a battery of studies to define the relative contributions of renal and non-renal AT1A receptors to physiological parameters that define the sodium sensitive phenotype. These experiments should allow us to separately assess the contributions of renal versus systemic AT1A receptors to circulatory homeostasis with a specificity that has not been possible previously.