High salt induces autocrine actions of ET-1 on inner medullary collecting duct NO production via upregulated ETB receptor expression.
The collecting duct endothelin-1 (ET-1), endothelin B (ETB) receptor, and nitric oxide synthase-1 (NOS1) pathways are critical for regulation of fluid-electrolyte balance and blood pressure control during high-salt feeding. ET-1, ETB 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 ETB receptor during high-salt feeding. We determined that after 7 days of a high-salt diet (HS7), there was a shift to 100% ETB 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 ETB receptor. ETB 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 ETB receptor are critical for IMCD NO production, facilitating inhibition of ion reabsorption.
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Kelly Anne
KA
Hyndman
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Courtney
C
Dugas
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
Alexandra M
AM
Arguello
Pharmacology and Experimental Therapeutics, Louisiana State University Health Science Center, New Orleans, Louisiana; and.
Traci T
TT
Goodchild
Department of Medicine, Augusta University, Augusta, Georgia;
Kathleen M
KM
Buckley
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Augusta University, Augusta, Georgia;
Mariah
M
Burch
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas; and International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
Masashi
M
Yanagisawa
Section of Cardio-Renal Physiology and Medicine, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama; Department of Medicine, Augusta University, Augusta, Georgia; jenniferpollock@uabmc.edu.
Jennifer S
JS
Pollock
D000818:Animals; D019898:Autocrine Communication / Q000502:physiology*; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D007685:Kidney Tubules, Collecting / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000493:pharmacokinetics*; D015854:Up-Regulation / Q000502:physiology
C000602969:EDNRB protein, mouse; D019332:Endothelin-1; D044023:Receptor, Endothelin B; D017673:Sodium Chloride, Dietary; D009569:Nitric Oxide
ETB receptor; collecting duct; endothelin-1; high-salt diet; nitric oxide