title: MMP-9- and NMDA receptor-mediated mechanism of diabetic renovascular remodeling and kidney dysfunction: hydrogen sulfide is a key modulator.
abstract: Previously we reported that matrix metalloproteinase-9 (MMP-9) plays an important role in extracellular matrix (ECM) remodeling in diabetic kidney. Induction of NMDA-R and dysregulation of connexins (Cxs) were also observed. We concluded that this was due to decreased H2S production by downregulation of CBS and CSE enzymes. However, the potential role of H2S to mitigate ECM dysregulation and renal dysfunction was not clearly understood. The present study was undertaken to determine whether H2S supplementation reduces MMP-9-induced ECM remodeling and dysfunction in diabetic kidney. Wild type (C57BL/6J), diabetic (Akita, C57BL/6J-Ins2(Akita)), MMP-9 knockout (MMP-9(-/-), M9KO) and double KO of Akita/MMP-9(-/-) (DKO) mice were treated without or with 0.005 g/l of NaHS (as a source of H2S) in drinking water for 30 days. Decreased tissue production and plasma content of H2S in Akita mice were ameliorated with H2S supplementation. Dysregulated expression of MMP-9, CBS, CSE, NMDA-R1 and Cxs-40, -43 was also normalized in Akita mice treated with H2S. In addition, increased renovascular resistive index (RI), ECM deposition, plasma creatinine, and diminished renal vascular density and cortical blood flow in Akita mice were normalized with H2S treatment. We conclude that diminished H2S production in renal tissue and plasma levels in diabetes mediates adverse renal remodeling, and H2S therapy improves renal function through MMP-9- and NMDA-R1-mediated pathway.
authors: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, KY 40292, USA.
authors: Sourav
authors: S
authors: Kundu
authors: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, KY 40292, USA.
authors: Sathnur
authors: S
authors: Pushpakumar
authors: Department of Physiology and Biophysics, University of Louisville, School of Medicine, Louisville, KY 40292, USA. Electronic address: u0sen001@louisville.edu.
authors: Utpal
authors: U
authors: Sen
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism*; D005109:Extracellular Matrix; D006862:Hydrogen Sulfide / Q000378:metabolism*; D007668:Kidney / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013440:Sulfides
chemical_list: D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide; D020780:Matrix Metalloproteinase 9; D016194:Receptors, N-Methyl-D-Aspartate; D013440:Sulfides; C501830:Mmp9 protein, mouse; C025451:sodium bisulfide
keywords: Collagen–elastin; Connexins; Diabetes; Extracellular matrix; Hydrogen sulfide; Matrix metalloproteinase; Nephropathy; Renal microvasculature