Urokinase Receptor Deficiency Accelerates Renal Fibrosis in Obstructive Nephropathy

• DOI: 10.1097/01.asn.0000064292.37793.fb
• Publication Date: 2004-10-23T14:37:06Z
• Authors: Guoqiang Zhang; Heungsoo Kim; Xiaohe Cai; Jesús M. López-Guisa; Charles E. Alpers; Youhua Liu; Peter Carmeliet; Allison A. Eddy
• Keywords: Extracellular Matrix Proteins; Genotype; Hepatocyte Growth Factor; Gene Expression; Receptors, Cell Surface; Fibrosis; Collagen Type I; Fibronectins; Receptors, Urokinase Plasminogen Activator; Mice, Inbred C57BL; Transforming Growth Factor beta1; Mice; Plasminogen Activators; 03 medical and health sciences; Kidney Tubules; 0302 clinical medicine; Transforming Growth Factor beta; Endopeptidases; Animals; RNA, Messenger; Low Density Lipoprotein Receptor-Related Protein-1; Procollagen

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