AT1 Receptors in Renal Microvascular Physiology

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DESCRIPTION (provided by applicant): Angiotensin (Ang) II has powerful effects on the kidney which are mediated primarily by the AT1 receptor. There are 2 unique AT1 receptor subtypes in rodents, AT1A and AT1B, which cannot be distinguished using pharmacological antagonists. Accordingly, the long term goal of this project is to determine the contribution of AT1A and AT1B receptors in mediating AnglI actions on renal microvascular function. The overall hypothesis to be tested is that the distribution of the AT1 A and AT1 B receptors along the renal microvasculature is not uniform; afferent arterioles have both AT1A and AT1 B subtypes, whereas effereni arterioles have only the AT1A receptor subtype. Therefore, the compensatory functions of the AT1A and AT1B receptors are restricted to the preglomerular vasculature. The hypothesis will be tested in the following specific aims: 1) To map the distribution of the ATIA and ATIB receptors on the pre- and postglomerular vasculature; 2) To elucidate the mechanism of calcium signaling evoked by activation of afferent and efferent arteriolar AT1A and AT1B receptors; 3) To determine the changes in microvascular AT1A and AT1B receptor expression and function in response to alterations in circulating Angli levels; and 4) To examine the functional consequences of renal microvascular AT1 receptor absence on the activity of counterregulatory vasodilatory actions of nitric oxide (NO) derived from neuronal (nNOS) and/or endothelial (eNOS) nitric oxide synthases. Mice with targeted disruption of AT1A and/or AT1B receptors will be studied to discern the functions of the AT1 receptor subtypes. Angli responses will be determined by direct visualization of preglomerular (arcuate, interlobular artery, afferent arteriole) and postglomerular (efferent arteriole, descending vasa recta) vasculature using the mouse in vitro blood perfused juxtamedullary nephron technique. Regulation of AT1 receptor subtype microvascular function and mRNA and protein expression/localization will be determined during chronically altered Angil levels mediated by varied salt intake, angiotensin converting enzyme inhibition, and Angil infusion. The interaction of AT1 receptors and NO derived from nNOS and eNOS on renal microvascular function will be evaluated by pharmacological approaches. The results of these studies will delineate the complex, overlapping, and distinct functions of AT1 receptors in controlling renal microvascular hemodvnamics.