Prostaglandin E2 is the major prostanoid synthesized along the nephron and plays an essential role in regulating renal hemodynamics and epithelial Na+ absorption. These effects of PGE2 may contribute to natriuresis, thereby reducing blood pressure, or be pro-hypertensive, by increasing renin release and epithelial Na+ absorption. PGE2 action is mediated by at least four E-prostanoid receptors: designated EP1, EP2, EP3, and EP4. EP2 and EP4 receptors stimulate cAMP, while EP1 and EP3 receptors signal vial phosphatidylinositol hydrolysis (PIP2) hydrolysis and the inhibitory protein Gi respectively. This proposal will test the hypothesis that the net effect of PGE2 on Na+ absorption and blood pressure, depends upon which renal EP receptor predominates, focusing on the roles of EP1 and EP4 receptors. We hypothesize that EP1 receptor activation contributes to PGE2 dependent natriuresis and is thereby anti-hypertensive.
Specific aim number 1 will test this hypothesis by generating mice with targeted disruption of the EP1 receptor gene (Ptgerep1). Effects of dietary Na+ intake and mineralocorticoid status on systemic blood pressure, glomerular filtration rate and transport in microperfused nephron segments will be assessed in intact wild type and ptgerep1 (-/-) mice. The effects of dietary Na+ intake on EP1 receptor expression will also be examined. Conversely we hypothesize EP4 receptor activation is pro-hypertensive. Functional evidence suggests EP4 receptor is expressed along the nephron: in collecting duct, and thick ascending limb. Since EP4 increases cAMP it may enhance water and Na reabsorption in these segments.
In specific aim number 2 the role of the EP4 receptor in regulating cortical thick limb and collecting duct transport will be assessed. Regulation of EP4 receptor by dietary Na+ intake will also be examined using reagents to define both receptor mRNA and protein expression. These studies will utilize new anti-EP-receptor antibodies generated to the entire receptor protein. Reagents for examining EP2 and EP3 receptors are also available. Finally we will characterize the functional consequences of over-expressing the collecting duct EP4 receptor in a transgenic mouse. These studies should help elucidate the role of EP receptors in renal Na+ homeostasis.
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