ANGIOTENSIN RECEPTOR GENES AND BLOOD PRESSURE REGULATION

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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.