title: Matrix metalloproteinase-9 deficiency attenuates diabetic nephropathy by modulation of podocyte functions and dedifferentiation.
abstract: Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.
authors.affiliation: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Szu-Yuan
authors.initials: SY
authors.lastname: Li
authors.affiliation: Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital and Institute of Anatomy and Cell Biology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: An-Hang
authors.initials: AH
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Tarng
authors.affiliation: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wu-Chang
authors.initials: WC
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chih-Ching
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital, Institute and Department of Pharmacology, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, The Institute of Engineering in Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Geert
authors.initials: G
authors.lastname: Schmid-Schönbein
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital, Institute of Clinical Medicine, and Cardiovascular Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D000419:Albuminuria / Q000201:enzymology; D000818:Animals; D054337:Cell Dedifferentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism / Q000652:urine; D051379:Mice; D018345:Mice, Knockout; D050199:Podocytes / Q000201:enzymology* / Q000473:pathology* / Q000502:physiology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse