Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy.
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 microg/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 alpha2-antiplasmin. Worse renal fibrosis in the uPAR-/- mice appears to be TGF-beta-independent, as TGF-beta activity was actually reduced by 65% in the -/- mice despite similar renal TGF-beta1 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.
Zhang
Guoqiang
G
Division of Nephrology, University of Washington, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105, USA.
Kim
Heungsoo
H
Cai
Xiaohe
X
López-Guisa
Jesús M
JM
Alpers
Charles E
CE
Liu
Youhua
Y
Carmeliet
Peter
P
Eddy
Allison A
AA
D000818:Animals; D024042:Collagen Type I / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis; D015870:Gene Expression; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000235:genetics; D007684:Kidney Tubules / Q000473:pathology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010960:Plasminogen Activators / Q000235:genetics; D011347:Procollagen / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics*; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014517:Ureteral Obstruction / Q000473:pathology* / Q000503:physiopathology*; D000979:alpha-2-Antiplasmin / Q000235:genetics
D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C524899:Plaur protein, mouse; D011347:Procollagen; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000979:alpha-2-Antiplasmin; D017228:Hepatocyte Growth Factor; D010450:Endopeptidases; D010960:Plasminogen Activators