ANGIOTENSIN RECEPTOR GENES AND BLOOD PRESSURE REGULATION

在上一个资助期，我们开发并表征了两种鼠AT1受体基因Agtr1a和Agtr1b靶向突变的小鼠模型。这些研究表明：（a）AT 1受体基因在血压和钠稳态中的重要性（B）两种AT 1受体基因的生理重要性的等级（Agtr1 a> Agtr1 B）（c）AT 1受体维持肾脏中血管和乳头状结构的基本作用和AT 1受体信号传导在肾脏中调节血压的关键作用。在本申请中，我们将继续研究AT1受体基因的生理作用，重点是它们在肾脏中的作用。AT1受体在肾脏的不同细胞区室中表达，我们认为这些表达模式反映了AT1受体调节肾脏结构和功能的不同作用。我们将通过以下具体目标来检验这一假设，并使用转基因小鼠模型来确定这些细胞区室对维持血压的贡献：（1）使用在先前资助期开发的交叉移植方法来表征仅在肾脏中缺乏或表达AT 1受体的小鼠的生理反应。(2)确定肾脏上皮细胞表达的AT1受体对维持血压钠稳态的作用。(3)确定血管平滑肌细胞中AT1受体的表达是否足以恢复缺乏AT1A受体的小鼠的正常血压水平。(4)目的：明确肾组织特异性表达AT 1受体在预防AT 1受体缺陷所致严重肾脏结构异常中的作用。这些研究将确定肾脏中AT1受体信号传导的生理重要性，并将比较AT1受体在调节血压中的上皮和血管作用的相对贡献。

In the previous funding period, we developed and characterized mouse models with targeted mutations of the two murine AT1 receptor genes, Agtr1a and Agtr1b. These studies demonstrated: (a) the importance of AT1 receptor genes in blood pressure and sodium homeostasis (b) a hierarchy for physiological importance of the two AT1 receptor genes (Agtr1a>>>Agtr1b) (c) the essential actions of AT1 receptors to maintain vascular and papillary structures in the kidney and the key role of AT1 receptor signaling in the kidney to regulate blood pressure. In this application, we will continue our studies of the physiological roles of AT1 receptor genes focusing on their actions in the kidney. AT1 receptors are expressed in distinct cellular compartments in the kidney and we posit that these expression patterns reflect distinct actions of AT1 receptors to regulate kidney structure and function. We will test this hypothesis and define the contribution of these cellular compartments to maintenance of blood pressure using transgenic mouse models through the following specific aims: (1) Using a cross-transplantation approach that was developed in the previous funding period, to characterize physiological responses of mice that lack or express AT1 receptors only in the kidney. (2) To determine contribution of AT1 receptors expressed in epithelial compartments in the kidney to maintaining blood pressure sodium homeostasis. (3) To determine whether expression of AT1 receptors in vascular smooth muscle cells is sufficient to restore normal levels of blood pressure in mice that otherwise lack AT1A receptors. (4) To define the role of tissue specific expression of AT1 receptors in preventing the severe renal structural abnormalities caused by AT1 receptor-deficiency. These studies will define the physiological importance of AT1 receptor signaling in the kidney and will compare the relative contribution of epithelial and vascular actions of AT1 receptors in regulating blood pressure.