RENAL AT1A RECEPTORS AND REGULATION OF BLOOD PRESSURE

钠敏感型高血压是一种常见的临床疾病。而钠 敏感性是一种遗传特征，它在人类中的遗传原因是 默默无闻。肾素-血管紧张素系统是一种重要的生理学 血压和钠稳态的调节剂。然而，一个角色是 肾素-血管紧张素系统在钠敏感性发病机制中的作用 还没有被具体描述。这些研究的目的是 确定AT1a受体基因在调节细胞周期中的作用 定义钠敏感性的生理反应。在这些研究中， 我们将检验AT1a受体基因座(Agtr1a)， 尤其是Agtr1A在肾脏中的表达，是中枢的 在调节血压和钠稳态方面的重要性。我们会 使用表达Agtr1A基因的小鼠模型来实现这一点 已经通过胚胎中的同源重组进行了特定的改变 干细胞。我们的第一个明确目标是检查亲属 AT1a受体对钠和血压的作用 通过检测缺乏AT1a受体的小鼠对 盐摄入量和容量状态、DOCA盐以及药理学的变化 其他血管紧张素受体和血管活性系统的操作。我们的 第二个特定目标是评估肾脏AT1a受体的作用。二 将使用免费的方法。首先，我们将进行肾脏手术 缺失Agtr1A(-/-)小鼠间的交叉移植实验 AT1a受体和野生型对照。第二，使用一种新的基因 有针对性的策略，我们将开发转基因小鼠品系，表达 AT1a受体受肾脏特异性启动子的控制。这个 转基因动物将与Agtr1A(-/-)系杂交，以获得 仅在近端肾小管上皮细胞表达AT1a受体的小鼠 细胞。通过这种方式，我们可以测试管状AT1a受体的能力 以刺激体内钠的重吸收。这些动物将暴露在 一系列研究确定了肾脏和肾脏的相对贡献 非肾脏AT1a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 分别评估肾脏和全身AT1a的作用 循环动态平衡的受体具有前所未有的特异性 以前有可能。

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.