A central role for prostaglandins in regulating blood pressure and renal salt and water homeostasis has been firmly established both from laboratory work and clinical experience using cyclooxygenase inhibiting NSAIDs. Renal side effects of NSAIDs are observed in as many as 10% of the elderly population, and can significantly limit their use. Development of renal sparing anti-inflammatory drugs would provide a significant advance for the more than 50 million Americans currently taking NSAIDs. The purpose of this proposal is to identify the specific G-protein coupled prostaglandin receptors that mediate the ability of the healthy kidney to maintain normal blood pressure and salt balance. These studies will utilize new receptor-specific reagents including knockout mice and the experimental agonists and antagonists to delineate the roles of the FP, EP1 and EP3 receptors. Although cellular data suggest important roles for the EP1 and EP3 receptors in regulating Na+ and water balance in the collecting duct, there is not a dramatic renal phenotype in mice when these receptors are blocked or genetically disrupted in vivo. In contrast the while the FP receptor is abundant in the kidney its functional role remains undetermined.
Specific Aim #1 is to characterize the cellular effects of FP and EP3 receptors on Na+ and H2O transport in distal tubule segments. These studies will utilize cell culture and in vitro microperfused tubules to assess the epithelial transport effects of FP selective reagents.
Specific Aim #2 will examine the role of the FP receptor in regulating renal function in the intact animal. These studies will utilize FP receptor knockout mice. Finally in specific aim #3, we will test the hypothesis that overlapping function of FP, EP3 and EP1 receptors contributes to the relatively mild phenotype observed in EP1 and EP3 null mice. These studies will characterize the regulation of blood pressure and renal salt excretion in FP, EP1 and EP3 compound null mice. Through these studies we hope to identify the pathway through which suppression of prostanoid products by cyclooxygenase inhibitors results in sodium retention.
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