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Endogenous urokinase lacks antifibrotic activity during progressive renal injury

Department of Pediatrics, Children's Hospital and Regional Medical Center, Division of Nephrology and University of Washington, Seattle, Washington

Submitted 23 September 2006 ; accepted in final form 8 March 2007

Interstitial fibrosis is a universal feature of progressive kidney disease. Urokinase-type plasminogen activator (uPA) is thought to participate for several reasons: 1) uPA is produced predominantly in kidney, 2) its inhibitor plasminogen activator inhibitor-1 (PAI-1) is a strong promoter of interstitial fibrosis, whereas its receptor (uPAR) attenuates renal fibrosis, 3) uPA reduces fibrosis in liver and lung, and 4) uPA can activate hepatocyte growth factor (HGF), a potent antifibrotic growth factor. The present study tested the hypothesis that endogenous uPA reduces fibrosis severity by investigating the unilateral ureteral obstruction (UUO) model in wild-type (WT) and uPA–/– mice. Several outcomes were measured: renal collagen 3–21 days after UUO, macrophage accumulation (F4/80 Western blotting), interstitial myofibroblast density (-smooth muscle actin immunostaining), and tubular injury (E-cadherin and Ksp-cadherin Western blotting). None of these measures differed significantly between WT and uPA–/– mice. uPA genetic deficiency was not associated with compensatory changes in renal uPAR mRNA levels, PAI-1 protein levels, or tissue plasminogen activator activity levels after UUO. Despite the known ability of uPA to activate latent HGF, immunoblotting failed to detect significant differences in levels of the active HGF -chain and phosphorylated cMET (the activated HGF receptor) between the WT and uPA–/– groups. These findings suggest that the profibrotic actions of PAI-1 are uPA independent and that an alternative pathway must activate HGF in kidney. Finally, these results highlight a significant organ-specific difference in basic fibrogenic pathways, as enhanced uPA activity has been reported to attenuate pulmonary and hepatic fibrosis.

renal interstitial fibrosis; unilateral ureteral obstruction; serine protease

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