title: Autocrine inhibition of Na+/K(+)-ATPase by nitric oxide in mouse proximal tubule epithelial cells.
abstract: An inducible nitric oxide synthase has recently been described in proximal tubule epithelium. To investigate the effects of proximal tubule NO on Na+/K(+)-ATPase, we induced NO production in mouse proximal tubule epithelial cells by treatment with lipopolysaccharide (LPS) and interferon-gamma (IFN gamma) followed by determinations of ouabain-sensitive ATPase activity. Na+/K(+)-ATPase activity decreased after 4 h of LPS/IFN gamma treatment, reaching maximal inhibition after 24 h (34% reduction in activity). The inhibition of Na+/K(+)-ATPase activity by LPS/IFN gamma was prevented by simultaneous incubation with N omega-nitro L-arginine and markedly blunted by removal of L-arginine from the medium. The NO donors sodium nitroprusside and SIN-1 also inhibited Na+/K(+)-ATPase activity to a similar extent than LPS/IFN gamma. However, treatment with 8-pCPT-cGMP only modestly reduced Na+/K(+)-ATPase activity. Interestingly, superoxide dismutase prevented the inhibitory effects of NO on Na+/K(+)-ATPase activity, suggesting a role for peroxynitrite in this inhibition. We conclude that NO generated by mouse proximal tubule epithelial cell iNOS inhibits Na/K ATPase activity in an autocrine fashion and that this inhibition is accompanied by a reduction in Na-dependent solute transport.
authors.affiliation: Department of Pharmacology, University of Florida College of Medicine, Gainesville, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Guzman
authors.forename: M Z
authors.initials: MZ
authors.lastname: Fang
authors.forename: S S
authors.initials: SS
authors.lastname: Tang
authors.forename: J R
authors.initials: JR
authors.lastname: Ingelfinger
authors.forename: L C
authors.initials: LC
authors.lastname: Garg
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis*; D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004790:Enzyme Induction; D004848:Epithelium / Q000187:drug effects / Q000201:enzymology; D007371:Interferon-gamma / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000201:enzymology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase; D019335:Nitroarginine; D009761:Nystatin / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D013873:Thionucleotides; D009761:Nystatin; D019335:Nitroarginine; D009569:Nitric Oxide; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; D000594:Amino Acid Oxidoreductases; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP