ANGIOTENSIN RECEPTOR GENES AND BLOOD PRESSURE REGULATION

在之前的资助期间，我们开发了两个小鼠AT1受体基因Agtr1a和Agtr1b的靶向突变的小鼠模型，并对其进行了表征。这些研究表明：(A)AT1受体基因在血压和钠稳态中的重要性；(B)两个AT1受体基因(Agtr1a和gt；&gt；&gt；Agtr1b)的生理重要性等级；(C)AT1受体在维持肾脏血管和乳头结构方面的基本作用，以及AT1受体信号在肾脏调节血压方面的关键作用。在这一应用中，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受体在肾脏不同的细胞室中表达，我们假设这些表达模式反映了AT1受体调节肾脏结构和功能的不同行为。我们将验证这一假说，并通过以下特定目的使用转基因小鼠模型来确定这些细胞间隔对维持血压的贡献：(1)使用在上一个资助期开发的交叉移植方法，来表征只在肾脏中缺乏或表达AT1受体的小鼠的生理反应。(2)探讨AT1受体在维持血压钠稳态中的作用。(3)确定血管平滑肌细胞AT1受体的表达是否足以使缺乏AT1a受体的小鼠恢复正常血压水平。(4)明确AT1受体的组织特异性表达在预防AT1受体缺陷引起的严重肾脏结构异常中的作用。这些研究将确定AT1受体信号在肾脏中的生理重要性，并将比较AT1受体在调节血压中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.