CONSTITUTIVE EXPRESSION OF HGF MODULATES RENAL EPITHELIAL-CELL PHENOTYPE AND INDUCES C-MET AND FIBRONECTIN EXPRESSION

Hepatocyte growth factor (HGF) is a potent renotropic factor that has been shown to play important roles in kidney development and recovery from acute renal injury. To examine the effects of HGF on renal tubula r epithelium, we generated HGF-producing renal epithelial cells by sta bly transfecting mIMCD-3 and OK cells with an expression plasmid conta ining human HGF cDNA. Expression of HGF in the transfected cells was c onfirmed by detection of HGF mRNA by Northern blot analysis and detect ion of HGF secretion into the conditioned medium by ELISA. HGF-transfe cted cells exhibited fibroblast-like, scattered morphology and increas ed cell motility. They formed branching tubules when grown in 3-D coll agen gel. In addition, HGF-producing cells grew faster than their pare ntal cells, but failed to form colonies in soft agar. These phenotypic changes were inhibited by a specific, neutralizing anti-HGF antibody. Interestingly, both c-met transcript and c-met protein were increased in HGF-transfected cells, suggesting that HGF amplifies its own actio n via stimulation of c-met expression. Autocrine expression of HGF and c-met in renal epithelial cells also stimulated fibronectin gene expr ession, which was totally blocked by incubation with a neutralizing an ti-HGF but not a pan-specific anti-TGF-beta antibody, suggesting that it is independent of TGF-beta production. Our data demonstrate that HG F as a single factor stimulates renal epithelial cell proliferation, m igration, differentiation, and extracellular matrix remodeling, making it uniquely suited to promote renal tubulogenesis during development, as well as to reconstitute tubular integrity following acute injury, (C) 1998 Academic Press.