title: Matrix metalloproteinase-12 deficiency attenuates experimental crescentic anti-glomerular basement membrane glomerulonephritis.
abstract: OBJECTIVE
  Matrix metalloproteinase-12 (MMP-12; macrophage elastase) is an enzyme that can cleave various extracellular matrix proteins and is required for macrophage infiltration and pulmonary fibrosis in experimental emphysema. We have shown previously that MMP-12 is highly up-regulated in experimental anti-glomerular basement membrane (GBM) disease. The aim of this study was to determine whether MMP-12 is required for glomerular macrophage infiltration and crescent formation in anti-GBM glomerulonephritis.
  
  
  METHODS
  Accelerated anti-GBM disease was induced in groups of MMP-12 gene deficient mice (MMP-12-/-) and wild-type C57BL/6J controls, which were killed 12 days after injection of anti-GBM serum.
  
  
  RESULTS
  Wild-type and MMP-12-/- mice developed glomerular damage and glomerular tuft adhesions to Bowman's capsule. Both groups developed severe proteinuria. Wild-type mice also developed significant loss of renal function and crescents in 22% of glomeruli, which were associated with macrophage infiltration and Bowman's capsule rupture. In contrast, MMP-12-/- mice were partially protected from renal function decline, crescent formation and Bowman's capsule rupture. This was associated with reduced macrophage infiltration in both glomeruli and the interstitium, and with reduced expression of CCL2, TNF-α and iNOS mRNA in MMP-12-/- kidneys. In addition, KIM-1 mRNA levels were reduced in MMP-12-/- mice indicating less tubular damage.
  
  
  CONCLUSIONS
  These data demonstrate that endogenous MMP-12 facilitates macrophage accumulation and activation in anti-GBM glomerulonephritis which is required for glomerular crescent formation, Bowman's capsule rupture, tubular damage and renal function decline.
authors.affiliation: Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.|Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
authors.forename: Abu P
authors.initials: AP
authors.lastname: Abraham
authors.affiliation: Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.|Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Ma
authors.affiliation: Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.|Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
authors.forename: William R
authors.initials: WR
authors.lastname: Mulley
authors.affiliation: Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.|Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Nikolic-Paterson
authors.affiliation: Department of Nephrology, Monash Medical Centre, Melbourne, Victoria, Australia.|Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
authors.forename: Greg H
authors.initials: GH
authors.lastname: Tesch
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D007678:Kidney Glomerulus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000201:enzymology* / Q000473:pathology; D053508:Matrix Metalloproteinase 12 / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011507:Proteinuria / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D053508:Matrix Metalloproteinase 12; C000602031:matrix metallopeptidase 12, mouse
keywords: glomerular crescent; glomerulonephritis; kidney disease; macrophage; matrix metalloproteinase-12