ANGIOTENSIN RECEPTOR IN RENAL MICROVASCULAR PHYSIOLOGY

Tulane University Of Louisiana, New Orleans LA

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Abstract

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 Angll actions on renal microvascular function. The overa I hypothesis to be tested is that the distribution of the AT1A and ATIB receptors along the renal microvasculature is not uniform; afferent arterioles have both AT1A and AT1B subtypes, whereas efferent arterioles have only the ATIA 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 characterize the distribution of the AT1A and AT1B receptors on the preand postglomerular vasculature; 2) To determine the changes in microvascular ATIA and AT1B receptor expression and function in response to alterations in circulating Angll levels; and 3) To delineate 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. Angll 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 uxtamedullary nephron technique. Regulation of AT1 receptor subtype microvascular function and RNA and protein expression/localization will be determined during chronically altered Angll levels mediated by varied salt intake, angiotensin converting enzyme inhibition, and Angll infusion. The interaction of AT1 receptors and nitric oxide 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.