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

Hak Joo Lee, Doug Yoon Lee, Meenalakshmi M. Mariappan, Denis Feliers, Goutam Ghosh-choudhury, Hanna E. Abboud, Yves Gorin, Balakuntalam S Kasinath

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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 whetherH2S 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 glucoseinduced NOX4 expression. NaHS inhibition of high glucoseinduced NOX4 expression was abrogated by N(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.

Original languageEnglish (US)
Pages (from-to)5665-5675
Number of pages11
JournalJournal of Biological Chemistry
Volume292
Issue number14
DOIs
StatePublished - Apr 7 2017

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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