title: Hydrogen sulfide deficiency and diabetic renal remodeling: role of matrix metalloproteinase-9.
abstract: Matrix metalloproteinase-9 (MMP-9) causes adverse remodeling, whereas hydrogen sulfide (H2S) rescues organs in vascular diseases. The involvement of MMP-9 and H2S in diabetic renovascular remodeling is, however, not well characterized. We determined whether MMP-9 regulates H2S generation and whether H2S modulates connexin through N-methyl-d-aspartate receptor (NMDA-R)-mediated pathway in the diabetic kidney. Wild-type (WT, C57BL/6J), diabetic (Akita, C57BL/6J-Ins2(Akita)), MMP-9(-/-) (M9KO), double knockout (DKO) of Akita/MMP-9(-/-) mice and in vitro cell culture were used in our study. Hyperglycemic Akita mice exhibited increased level of MMP-9 and decreased production of H2S. H2S-synthesizing enzymes cystathionine-β-synthase and cystathionine-γ-lyase were also diminished. In addition, increased expressions of NMDA-R1 and connexin-40 and -43 were observed in diabetic kidney. As expected, MMP-9 mRNA was not detected in M9KO kidneys. However, very thin protein expression and activity were detected. No other changes were noticed in M9KO kidney. In DKO mice, all the above molecules showed a trend toward baseline despite hyperglycemia. In vitro, glomerular endothelial cells treated with high glucose showed induction of MMP-9, attenuated H2S production, NMDA-R1 induction, and dysregulated conexin-40 and -43 expressions. Silencing MMP-9 by siRNA or inhibition of NMDA-R1 by MK801 or H2S treatment preserved connexin-40 and -43. We conclude that in diabetic renovascular remodeling MMP-9 plays a major role and that H2S has therapeutic potential to prevent adverse diabetic renal remodeling.
authors: Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky.
authors: Sourav
authors: S
authors: Kundu
authors: Sathnur B
authors: SB
authors: Pushpakumar
authors: Aaron
authors: A
authors: Tyagi
authors: Denise
authors: D
authors: Coley
authors: Utpal
authors: U
authors: Sen
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006030:Glycosuria, Renal / Q000235:genetics / Q000378:metabolism; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000098:blood supply / Q000166:cytology; D007687:Kidney Tubules, Proximal / Q000098:blood supply / Q000166:cytology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D006862:Hydrogen Sulfide; D020780:Matrix Metalloproteinase 9; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; C501830:Mmp9 protein, mouse
keywords: NMDA receptor; connexin; diabetes; hydrogen sulfide; matrix metalloproteinase; renal remodeling
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