Delayed treatment with plasminogen activator inhibitor-1 decoys reduces tubulointerstitial fibrosis.
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.
Gonzalez
Julien
J
INSERM, U858-I2MR - Equipe 5, 1 avenue Jean Poulhès, B.P. 84225, 31432 Toulouse Cedex 4, France.
Klein
Julie
J
Chauhan
Sharmila D
SD
Neau
Eric
E
Calise
Denis
D
Nevoit
Caroline
C
Chaaya
Rana
R
Miravete
Mathieu
M
Delage
Christine
C
Bascands
Jean-Loup
JL
Schanstra
Joost P
JP
Buffin-Meyer
Bénédicte
B
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
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