title: Delayed treatment with plasminogen activator inhibitor-1 decoys reduces tubulointerstitial fibrosis.
abstract: We examined the capacity of delayed inhibition of plasminogen activator inhibitor-1 (PAI-1) to reduce tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO) in mice. Small peptides mimicking parts of urokinase (uPA) and tissular plasminogen activator (tPA) and serving as decoy molecules for PAI-1 were administered daily during the late stages (3 to 8 days) of UUO. Treatment with PAI-1 decoys reduced interstitial deposition of fibronectin, collagen III and collagen IV without changes in macrophage and myofibroblast infiltration. Interestingly, while PAI-1 activity was reduced and the combined uPA and tPA activity was increased, the antifibrotic effect was obtained without modification of plasmin activity but with increased of hepatocyte growth factor (HGF) expression. We show for the first time that treatment with small PAI-1 decoy peptides reduces established tubulointerstitial fibrosis. This protective effect probably resulted from increased degradation of the extracellular matrix by an HGF dependent mechanism.
authors.affiliation: INSERM, U858-I2MR - Equipe 5, 1 avenue Jean Poulhès, B.P. 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Julie
authors.initials: J
authors.lastname: Klein
authors.forename: Sharmila D
authors.initials: SD
authors.lastname: Chauhan
authors.forename: Eric
authors.initials: E
authors.lastname: Neau
authors.forename: Denis
authors.initials: D
authors.lastname: Calise
authors.forename: Caroline
authors.initials: C
authors.lastname: Nevoit
authors.forename: Rana
authors.initials: R
authors.lastname: Chaaya
authors.forename: Mathieu
authors.initials: M
authors.lastname: Miravete
authors.forename: Christine
authors.initials: C
authors.lastname: Delage
authors.forename: Jean-Loup
authors.initials: JL
authors.lastname: Bascands
authors.forename: Joost P
authors.initials: JP
authors.lastname: Schanstra
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Buffin-Meyer
mesh_terms: D000818:Animals; D024061:Collagen Type III / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D005341:Fibrinolysin / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism* / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D010455:Peptides / Q000494:pharmacology*; D058258:Serpin E2; D015843:Serpins; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D024061:Collagen Type III; D024141:Collagen Type IV; D005353:Fibronectins; D010455:Peptides; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D017228:Hepatocyte Growth Factor; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator