High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ET_B receptor expression

The collecting duct endothelin-1 (ET-1), endothelin B (ET_B) receptor, and nitric oxide synthase-1 (NOS1) pathways are critical for regulation of fluidelectrolyte balance and blood pressure control during high-salt feeding. ET-1, ET_B receptor, and NOS1 are highly expressed in the inner medullary collecting duct (IMCD) and vasa recta, suggesting that there may be cross talk or paracrine signaling between the vasa recta and IMCD. The purpose of this study was to test the hypothesis that endothelial cell-derived ET-1 (paracrine) and collecting duct-derived ET-1 (autocrine) promote IMCD nitric oxide (NO) production through activation of the ET_B receptor during high-salt feeding. We determined that after 7 days of a high-salt diet (HS7), there was a shift to 100% ET_B expression in IMCDs, as well as a twofold increase in nitrite production (a metabolite of NO), and this increase could be prevented by acute inhibition of the ET_B receptor. ET_B receptor blockade or NOS1 inhibition also prevented the ET-1-dependent decrease in ion transport from primary IMCDs, as determined by transepithelial resistance. IMCD were also isolated from vascular endothelial ET-1 knockout mice (VEETKO), collecting duct ET-1 KO (CDET-1KO), and flox controls. Nitrite production by IMCD from VEETKO and flox mice was similarly increased twofold with HS7. However, IMCD NO production from CDET-1KO mice was significantly blunted with HS7 compared with flox control. Taken together, these data indicate that during high-salt feeding, the autocrine actions of ET-1 via upregulation of the ET_B receptor are critical for IMCD NO production, facilitating inhibition of ion reabsorption.