Up-regulation of hepatocyte growth factor receptor: An amplification and targeting mechanism for hepatocyte growth factor action in acute renal failure

Background. Hepatocyte growth factor (HGF) and its c-met receptor comprise a signaling system that has been implicated in tissue repair and regenerati on. HGF action is specifically targeted to the damaged organ following inju ry; however, the mechanism underlying this important targeting process rema ins to be elucidated. We reasoned that induction of c-met expression might be a critical factor in determining the site specificity of this receptor-l igand system. To test this hypothesis, we examined changes in activity of t he HGF/c-met system in the folic acid model of acute tubular injury and rep air. Methods. Tissue HGF and c-met mRNA levels were detected by RNase protection assay and Northern blot analysis following acute renal injury induced by a single injection of folic acid. HGF and c-met proteins were examined by a specific enzyme immunoassay and Western blotting, respectively. C-met expre ssion and trans-activation were investigated by exposing renal epithelial m IMCD-3 cells to various cytokines in vitro. Results. Extremely rapid induction of renal HGF and c-met mRNA was observed beginning one hour following injection of folic acid. Circulating plasma H GF protein level rose dramatically (approximately 16-fold), peaking first a t two hours and again at 24 hours following injection. Despite elevated HGF mRNA in the kidney, total kidney HGF protein actually decreased significan tly at 24 hours following injury. On the other hand, both c-met mRNA and c- met protein were markedly increased in the kidney, where active renal tubul e repair and regeneration take place. In vitro studies suggested that incre ased levels of HGF, as well as other cytokines, might account for enhanced c-met expression in renal tubular epithelial cells. Pretreatment of the cel ls with actinomycin D totally blocked c-met induction, suggesting that indu ced c-met expression occurs primarily at the transcriptional level. Using a cloned region of the c-met promoter coupled to a reporter gene, we demonst rated that HGF directly stimulated c-met promoter transactivation in renal epithelial cells. Conclusion. These results suggest that local up-regulation of c-met transcr iption in the kidney is crucial to renal tubule repair and regeneration, no t only because it increases overall activity of this receptor-ligand system , but also as a mechanism targeting HGF action specifically to renal epithe lia.