End-stage renal disease (ESRD) is one of the most devastating diseases with great morbidity and mortality, and the number of patients is on the rise worldwide. Despite diverse primary etiologies, the pathogenesis of chronic renal diseases progressing to ESRD is a remarkably monotonous process characterized by relentless accumulation of extracellular matrix (ECM) leading to widespread tissue fibrosis. Thus, developing a scheme to inhibit fibrosis appears to be a key strategy for the treatment of chronic renal disease. Preliminary studies in our laboratory suggest that hepatocyte growth factor (HGF) is an important regulator of extracellular matrix turnover leading to inhibition of tissue fibrosis in animal model of renal diseases. Because exogenous HGF is very unstable in blood circulation due to the rapid clearance by liver, we recently develop a gene transfer strategy using naked plasmid vector resulting in efficient expression of HGF protein in vivo. Based on these results, we hypothesize that delivery of HGF gene is an effective therapeutic strategy for the treatment of chronic renal disease. In this application, we propose to administrate HGF gene into animal model of progressive renal disease to evaluate its therapeutic efficacy. We will investigate the mechanism underlying HGF ameliorating renal fibrosis by examining the regulation of myofibroblast activation and TGF-Beta1 signaling. These will be accomplished in the following three specific aims: 1) to evaluate the efficacy of HGF gene therapy for chronic renal fibrosis; 2) to investigate the role of HGF in renal myofibroblast activation; 3) to elucidate the molecular mechanism underlying HGF blocking pro-fibrogenic cytokine TGF-Beta1 signaling. These studies will provide fundamental information such as the feasibility and efficacy of HGF gene therapy for chronic renal diseases, and will eventually lead to new therapeutic strategies to human chronic renal fibrosis, which is otherwise incurable.
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