Endothelium-derived relaxing factor (EDRF) is a recently discovered paracrine hormone released from the endothelium lining the vasculature. EDRF has been shown to affect the renal vasculature, but a direct action on individual nephron segments has not been reported to date. Our hypothesis is that EDRF produced by renal endothelial cells inhibits fluid and sodium transport in the collecting duct system. This is based on 1) our preliminary data showing the EDRF inhibits transport in cultured collecting duct cells; 2) the proximity of renal vessels and nephrons; and 3) the fact that EDRF stimulates cGMP production in vascular tissue and CGMP inhibits transport in the collecting duct.
Our specific aims are to investigate: 1) the effects of EDRF on basal sodium and water transport; 2) vasopressin-stimulated transport of sodium and water; 3) if cGMP is the second messenger of EDRF; 4) the roles of protein kinases and phosphodiesterases in mediating the effects; and 5) if the sodium channel is phosphorylated in response to EDRF. We will use a variety of techniques including measurement of transepithelial fluxes of sodium and water; assay of cyclic nucleotides, kinases and phosphodiesterases; immunoprecipitation of the amiloride-sensitive sodium channel and Western blot analysis. The collecting duct system plays a pivotal role in the regulation of solute and water excretion and consequently blood pressure. EDRF may prove to be one of the most important regulators of collecting duct function and yet there is a paucity of data concerning the effects of EDRF on transport in this segment of the nephron.
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