HEPATOCYTE GROWTH-FACTOR STIMULATED RENAL TUBULAR MITOGENESIS - EFFECTS ON EXPRESSION OF C-MYC, C-FOS, C-MET, VEGF AND THE VHL TUMOR-SUPPRESSOR AND RELATED GENES

Hepatocyte growth factor (HGF/SF) is a potent renal proximal tubular c ell (PTEC) mitogen involved in renal development. HGF/SF is the functi onal ligand for the c-met proto-oncogene, and germline c-met mutations are associated with familial papillary renal cell carcinoma. Somatic von Hippel-Lindau disease tumour-suppressor gene (VHL) mutations are f requently detected in sporadic clear cell renal cell carcinomas (RCC), and germline VHL mutations are the commonest cause of familial clear cell RCC, pVHL binds to the positive regulatory components of the trim eric elongin (SIII) complex (elongins B and C) and has been observed t o deregulate expression of the vascular endothelial growth factor (VEG F) gene. HGF/SF has similarly been reported to up-regulate expression of the VEGF gene in non-renal experimental systems. To investigate the mechanism of HGF/SF action in PTECs and, specifically, to examine pot ential interactions between the HGF/c-met and the VHL-mediated pathway s for renal tubular growth control, we have isolated untransformed PTE Cs from normal kidneys, developed conditions for their culture in vitr o and used these cells to investigate changes in mRNA levels of the VH L, elongin A, B and C, VEGF, c-myc, c-fos and c-met genes after HGF/SF exposure. Significant elevations in the mRNA levels of VEGF, c-myc, c -fos, c-met and elongins A, B and C, but not VHL, were detected after HGF/SF stimulation of human PTECs (P < 0.02), with a consistent order of peak levels observed over successive replicates (c-fos at 1 h, VEGF at 2-4 h, c-myc, at 4 h, followed by c-met and all three elongin subu nits at 8 h). This study highlights the spectrum of changes in gene ex pression observed in PTECs after HGF/SF stimulation and has identified possible candidate mediators of the HGF/SF-induced mitogenic response . Our evidence would suggest that the changes in PTEC VEGF expression induced by HGF/SF are mediated by a VHL-independent pathway.