ANGIOTENSIN RECEPTOR GENES AND BLOOD PRESSURE REGULATION

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DESCRIPTION: The renin-angiotensin system (RAS) plays a critical role in regulating blood pressure and sodium balance and these actions are mediated through angiotensin type I (AT1) receptors. In the kidney, the RAS acts through three distinct pathways that may influence sodium handling: (1) hemodynamic effects at the level of the glomerular circulation mediated by ATl receptors on renal vasculature (2) direct effects on sodium transport modulated by ATl receptors expressed on proximal tubular epithelial cells (3) regulation of sodium reabsorption in the distal nephron by aldosterone under the control of ATl receptors in the adrenal cortex. In the mouse, two separate ATl receptor genes control these functions: AgtrlA and AgtrlB. Using mouse models in which expression of these ATl receptor genes has been specifically altered using gene targeting, it is proposed to determine the role of ATl angiotensin receptor genes in regulating blood pressure through the following specific aims: Specific Aim I: To define the role of the ATlA receptor in renal adaptation to altered dietary sodium intake, the hypothesis that abnormal renal sodium handling contributes to sodium dependent blood pressure changes in the AgtrlA (-/-) mice will be studied. Specific Aim II: To examine the role of renal AgtrlA expression in the regulation of blood pressure, the contribution of renal ATlA receptors to the control of blood pressure in renal cross transplantation experiments between AgtrlA (+/+) and AgtrlA (-/-) mice will be determined. Specific Aim III: To determine the contribution of renal epithelial actions of angiotensin II to blood pressure and sodium homeostasis transgenic mice that express the ATlA receptor in the kidney only on epithelial cells in the proximal tubule will be developed. Specific Aim IV: To determine the role of AT1B receptors in blood pressure regulation in AgtrlA (-/-) mice, RAS regulation by dietary sodium, and blood pressure responses will be studied when AT1B receptors are inhibited or absent. Specific Aim V: To define the contribution of the AgtrlB gene to blood pressure regulation, mice with targeted disruption of the AgtrlB gene will be studied.