title: Hydrogen sulfide inhibits high glucose-induced NADPH oxidase 4 expression and matrix increase by recruiting inducible nitric oxide synthase in kidney proximal tubular epithelial cells.
abstract: High-glucose increases NADPH oxidase 4 (NOX4) expression, reactive oxygen species generation, and matrix protein synthesis by inhibiting AMP-activated protein kinase (AMPK) in renal cells. Because hydrogen sulfide (H2S) inhibits high glucose-induced matrix protein increase by activating AMPK in renal cells, we examined whether H2S inhibits high glucose-induced expression of NOX4 and matrix protein and whether H2S and NO pathways are integrated. High glucose increased NOX4 expression and activity at 24 h in renal proximal tubular epithelial cells, which was inhibited by sodium hydrosulfide (NaHS), a source of H2S. High glucose decreased AMPK phosphorylation and activity, which was restored by NaHS. Compound C, an AMPK inhibitor, prevented NaHS inhibition of high glucose-induced NOX4 expression. NaHS inhibition of high glucose-induced NOX4 expression was abrogated byN(ω)-nitro-l-arginine methyl ester, an inhibitor of NOS. NaHS unexpectedly augmented the expression of inducible NOS (iNOS) but not endothelial NOS. iNOS siRNA and 1400W, a selective iNOS inhibitor, abolished the ameliorative effects of NaHS on high glucose-induced NOX4 expression, reactive oxygen species generation, and, matrix laminin expression. Thus, H2S recruits iNOS to generate NO to inhibit high glucose-induced NOX4 expression, oxidative stress, and matrix protein accumulation in renal epithelial cells; the two gasotransmitters H2S and NO and their interaction may serve as therapeutic targets in diabetic kidney disease.
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.|the South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Hak Joo
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.
authors.forename: Doug Yoon
authors.initials: DY
authors.lastname: Lee
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.|the South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Meenalakshmi M
authors.initials: MM
authors.lastname: Mariappan
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.|the South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Denis
authors.initials: D
authors.lastname: Feliers
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.|the South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Goutam
authors.initials: G
authors.lastname: Ghosh-Choudhury
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.|the South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and.
authors.forename: Yves
authors.initials: Y
authors.lastname: Gorin
authors.affiliation: From the University of Texas Health Science Center, San Antonio, Texas 78229-3900 and Kasinath@uthscsa.edu.|the South Texas Veterans Health Care System, San Antonio, Texas 78229.
authors.forename: Balakuntalam S
authors.initials: BS
authors.lastname: Kasinath
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D003928:Diabetic Nephropathies / Q000201:enzymology / Q000473:pathology / Q000628:therapy; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000578:Amidines; D001596:Benzylamines; D016326:Extracellular Matrix Proteins; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D006862:Hydrogen Sulfide
keywords: AMP-activated kinase (AMPK); diabetic nephropathy; laminin; oxidative stress; reactive oxygen species (ROS)