Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy

Abstract

The urokinase cellular receptor (uPAR) recognizes the N-terminal growth factor domain of urokinase-type plasminogen activator (uPA) and is expressed by several cell types. The present study was designed to test the hypothesis that uPAR regulates the renal fibrogenic response to chronic injury. Groups of uPAR wild-type (+/+) and deficient (-/-) mice were investigated between 3 and 14 d after unilateral ureteral obstruction (UUO) or sham surgery. Not detected in normal kidneys, uPAR mRNA was expressed in response to UUO in the +/+ mice. By in situ hybridization, uPAR mRNA transcripts were detected in renal tubules and interstitial cells of the obstructed uPAR+/+ kidneys. The severity of renal fibrosis, based on the measurement of total collagen (13.5 ± 1.5 versus 9.8 ± 1.0 μg/mg kidney on day 14; -/- versus +/+) and interstitial area stained by Masson trichrome (22 ± 4% versus 14 ± 3% on day 14; -/- versus +/+) was significantly greater in the uPAR-/- mice. In the absence of uPAR, renal uPA activity was significantly decreased compared with the wild-type animals after UUO (62 ± 20 versus 135 ± 13 units at day 3 UUO; 74 ± 17 versus 141 ± 16 at day 7 UUO; 98 ± 20 versus 165 ± 10 at day 14 UUO; -/- versus +/+). In contrast, renal expression of several genes that regulate plasmin activity were similar in both genotypes, including uPA, tPA, PAI-1, protease nexin-1, and α2-antiplasmin. Worse renal fibrosis in the uPAR-/- mice appears to be TGF-β-independent, as TGF-β activity was actually reduced by 65% in the -/- mice despite similar renal TGF-β1 mRNA levels. Significantly lower levels of the major 2.3-kb transcript and the 69-kd active protein of hepatocyte growth factor (HGF), a known anti-fibrotic growth factor, in the uPAR-/- mice suggests a potential link between HGF and the renoprotective effects of uPAR. These data suggest that renal uPAR attenuates the fibrogenic response to renal injury, an outcome that is mediated in part by urokinase-dependent but plasminogen-independent functions.