Hydrogen Sulfide Inhibits High Glucose-induced NADPH Oxidase 4 Expression and Matrix Increment by Recruiting Inducible Nitric Oxide Synthase in the Kidney Proximal Tubular Epithelial Cells [Glycobiology and Extracellular Matrices]

High glucose increases NADPH oxidase 4 (NOX4) expression, reactive oxygen species (ROS) generation, and, matrix protein synthesis by inhibiting AMP-activated protein kinase (AMPK) in renal cells. Since hydrogen sulfide (H2S) inhibits high glucose-induced matrix protein increment by activating AMPK in renal cells, we examined if H2S inhibits high glucose induced expression of NOX4 and matrix protein and if H2S nitric oxide (NO) pathways are integrated. High glucose increased NOX4 expression and activity at 24 h in renal proximal tubular epithelial cells that was inhibited by sodium hydrosulfide (NaHS), a source of H2S. High glucose decreased AMPK phosphorylation and activity that 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 by L-NAME, an inhibitor of NO synthase (NOS). NaHS unexpectedly augmented the expression of inducible NOS (iNOS) but not eNOS; iNOS siRNA and 1400W, a selective iNOS inhibitor, abolished the ameliorative effects of NaHS on high glucose-induced NOX4 expression, ROS generation, and, matrix laminin expression. Thus, H2S recruits iNOS to generate NO in order 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.

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