The progression of chronic renal diseases is considered as an irreversible process that eventually leads to end-stage renal failure characterized by extensive tissue fibrosis. At present, chronic renal fibrosis is incurable and the incidence of affected patients is on the rise worldwide. In this study, 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 in the obstructed kidneys following intravenous injection of naked plasmid encoding human HGF. Delivery of human HGF gene induced a sustained activation of extracellular signal-regulated kinases-1 and -2 in the obstructed kidneys. Exogenous HGF expression dramatically inhibited alpha-smooth muscle actin expression, attenuated renal interstitial accumulation and deposition of collagen I and fibronectin. In addition, exogenous HGF suppressed renal expression 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.