RENAL AT1A RECEPTORS AND REGULATION OF BLOOD PRESSURE

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Sodium sensitive hypertension is a common clinical disorder. While sodium sensitivity is an inherited trait, its genetic causes in humans are obscure. The renin-angiotensin system is a critical physiological regulator of blood pressure and sodium homeostasis. However, a role for the renin-angiotensin system in the pathogenesis of sodium sensitivity has not been specifically delineated. The aim of these studies is to determine the role of the AT1A receptor gene in modulating the physiological responses that define sodium sensitivity. In these studies, we will test the hypothesis that the AT1A receptor gene locus (Agtr1A ), and in particular Agtr1A expression in the kidney, is of central importance in regulating blood pressure and sodium homeostasis. We will accomplish this using mouse models in which expression of the Agtr1A gene has been specifically altered using homologous recombination in embryonic stem cells. Our first specific aim is to examine the relative contribution of the AT1A receptor to sodium and blood pressure homeostasis by examining the response of mice lacking AT1A receptors to changes in salt intake and volume status, DOCA salt, and by pharmacologic manipulation of other angiotensin receptors and vasoactive systems. Our second specific aim is to assess the role of renal AT1A receptors. Two complimentary approaches will be used. First, we will perform renal cross-transplantation experiments between Agtr1A (-/-) mice that lack AT1A receptors and wild type controls. Second, using a novel gene targeting strategy, we will develop lines of transgenic mice that express AT1A receptors under the control of kidney specific promoters. The transgenic animals will be crossed with the Agtr1A (-/-)line to obtain mice that express AT1A receptors only on proximal tubular epithelial cells. In this way, we can test the capacity of tubular AT1A receptors to stimulate sodium reabsorption in vivo. The animals will be exposed to a battery of studies to define the relative contributions of renal and non-renal AT1A receptors to physiological parameters that define the sodium sensitive phenotype. These experiments should allow us to separately assess the contributions of renal versus systemic AT1A receptors to circulatory homeostasis with a specificity that has not been possible previously.