Mitogenic signaling of urokinase receptor-deficient kidney fibroblasts: actions of an alternative urokinase receptor and LDL receptor-related protein.

Zhang G, Cai X, López-Guisa JM, Collins SJ, Eddy AA
J Am Soc Nephrol. 2004 15 (8): 2090-102

PMID: 15284295 · DOI:10.1097/01.ASN.0000135057.41526.2C

The urokinase receptor (uPAR) attenuates myofibroblast recruitment and fibrosis in the kidney. This study examined the role of uPAR and its co-receptor LDL receptor-related protein (LRP) in the regulation of kidney fibroblast proliferation and extracellular signal-regulated kinase (ERK) signaling. Compared with uPAR+/+ cells, uPAR-/- kidney fibroblasts were hyperproliferative. UPAR-/- fibroblast proliferation was 60% inhibited by an ERK kinase inhibitor. LRP protein was reduced and extracellular accumulation of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) proteins were greater in uPAR-/- cultures. Addition of functional uPA protein or LRP antisense RNA significantly increased ERK signaling and cell mitosis in both genotypes. Enhanced uPAR-/- fibroblast proliferation was reversed by a recombinant nonfunctional uPA peptide. The density of cell-bound fluor-uPA was similar between uPAR-/- and uPAR+/+ fibroblasts (78 +/- 6 versus 92 +/- 16 units). These data suggest that uPAR-deficient kidney fibroblasts express lower levels of its scavenger co-receptor LRP, resulting in greater extracellular accumulation of uPA and PAI-1. Enhanced proliferation of uPAR-/- fibroblasts seems to be mediated by uPA-dependent ERK signaling via an alternative urokinase receptor.

MeSH Terms (18)

Animals Cell Division Cells, Cultured Fibroblasts Kidney Low Density Lipoprotein Receptor-Related Protein-1 MAP Kinase Signaling System Mice Mice, Inbred C57BL Mice, Mutant Strains Mitogen-Activated Protein Kinases Phenotype Phosphorylation Plasminogen Activator Inhibitor 1 Receptors, Cell Surface Receptors, Urokinase Plasminogen Activator Ureteral Obstruction Urokinase-Type Plasminogen Activator

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