Systemic administration of naked plasmid encoding hepatocyte growth factorameliorates chronic renal fibrosis in mice

The progression of chronic renal diseases Is considered as an irreversible process that eventually leads to end-stage renal failure characterized by e xtensive tissue fibrosis. At present, chronic renal fibrosis is incurable a nd the incidence of affected patients is on the rise worldwide. In this stu dy, we demonstrate that delivery of hepatocyte growth factor (HGF) gene via systemic administration of naked plasmid vector markedly ameliorated renal fibrosis in an animal model of chronic renal disease induced by unilateral ureteral obstruction. A high level of exogenous HGF protein was detected i n the obstructed kidneys following intravenous injection of naked plasmid e ncoding human HGF Delivery of human HGF gene induced a sustained activation of extracellular signal-regulated kinases-1 and -2 in the obstructed kidne ys. Exogenous HGF expression dramatically inhibited a-smooth muscle actin e xpression, attenuated renal interstitial accumulation and deposition of col lagen I and fibronectin. In addition, exogenous HGF suppressed renal expres sion of pro-fibrogenic cytokine TGF-beta1 and its type I receptor in vivo. These results suggest that systemic administration of naked plasmid vector introduces a high level of exogenous HGF to the diseased kidneys, and that HGF gene transfer may provide a novel therapeutic strategy for amelioration of chronic renal fibrosis in vivo.