title: Plasmin is not protective in experimental renal interstitial fibrosis.
abstract: BACKGROUND
  The plasminogen-plasmin system has potential beneficial or deleterious effects in the context of renal fibrosis. Recent studies have implicated plasminogen activators or their inhibitors in this process.
  
  
  METHODS
  The development of renal interstitial fibrosis was studied in mice genetically deficient in plasminogen (plg-/- mice) and littermate controls (plg+/+ mice) by inducing unilateral ureteric obstruction (UUO) by ligating the left ureter.
  
  
  RESULTS
  Collagen accumulation in the kidney was decreased in plg-/- mice at 21 days compared with plg+/+ mice by hydroxyproline assay (plg+/+ 19.0 +/- 1.2 microg collagen/mg tissue, plg-/- 15.6 +/- 0.5 microg collagen/mg tissue, P= 0.04). Macrophage accumulation in plg-/- mice was reduced at 21 days, consistent with a role for plasmin in macrophage recruitment in this model. Myofibroblast accumulation, assessed by the expression of alpha-smooth muscle actin (alpha-SMA), was similar in both groups at both time points. Endogenous plasmin played a role in the activation of transforming growth factor-beta (TGF-beta), as plg-/- mice had lower ratios of betaig-h3:TGF-beta1 mRNA than plg+/+ mice. Matrix metalloproteinase (MMP)-9 activity was unchanged in the absence of plasmin, but MMP-2 activity was decreased.
  
  
  CONCLUSIONS
  Plasminogen, the key proenzyme in the plasminogen-plasmin system, does not protect mice from experimental interstitial fibrosis and may have significant pathogenetic effects. These findings, together with other recently published studies in the biology of renal fibrosis, imply that effects of proteins such as plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator receptor (uPAR) on renal fibrosis occur independently from the generation of plasmin.
authors.affiliation: Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Kristy L
authors.initials: KL
authors.lastname: Edgtton
authors.forename: Renae M
authors.initials: RM
authors.lastname: Gow
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Kelly
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D000818:Animals; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005341:Fibrinolysin / Q000378:metabolism*; D005347:Fibroblasts / Q000473:pathology; D005355:Fibrosis; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008264:Macrophages / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D010958:Plasminogen / Q000172:deficiency / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000099222:betaIG-H3 Protein
chemical_list: D003094:Collagen; D016326:Extracellular Matrix Proteins; D005341:Fibrinolysin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010958:Plasminogen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099222:betaIG-H3 Protein; C508961:Tgfb1 protein, mouse