Chronic renal dysfunction is a progressive, degenerative disorder that ultimately results in acute renal failure and requires dialysis as an intervention, and renal transplantation as the only potential cure. Initiating conditions of renal dysfunction include ischemia, diabetes, underlying cardiovascular disease, or renal toxicity associated with certain chemotherapeutics, antibiotics, and radiocontrast agents. Most end-stage pathological changes include extensive fibrinogenesis, epithelial atrophy, and inflammatory cell infiltration into the kidneys. Scatter factor, also known as hepatocyte growth factor (SF/HGF), is a pleiotropic growth factor that induces the activation and proliferation of diverse cell types, largely through its mitogenic, motogenic, morphogenic, and anti-apoptotic activities. Several recently published studies have demonstrated the therapeutic potential of exogenously administered SF/HGF in the treatment of animal models of toxic, obstructive and ischemic renal disease. The clinical development of protein-based therapies has been hampered by potential immune responses, protein instability, and cost-prohibitive production schemes. We have developed a small molecule mimetic of SF/HGF, called C6, which holds significant potential to overcome these shortfalls. C6 recapitulates many of the bioactivities of SF/HGF, both in vitro and in vivo, by activation of the SF/HGF receptor, c-met. In order to explore further the therapeutic potential of C6 in renal dysfunction, we propose to evaluate the in vivo efficacy of C6 in chronic renal disease secondary to ureteral obstruction, renal ischemia, or heavy metal toxicity; determine the proteomic mechanism of action of the C6 in renal protection and regeneration; and determine the pharmacokinetics, biodistribution and toxicity of C6. It is our expectation that C6 will demonstrate efficacy similar to SF/HGF administration in the treatment of obstructive, ischemic and toxic renal injury, and will therefore hold significant clinical potential. These results will be significant, because a small molecule mimetic of the therapeutic effects of SF/HGF activity will eliminate many of the logistical shortcomings of protein-based therapeutics. Successful completion of the proposed studies is expected to provide sufficient data to seek regulatory approval for initiation of clinical trials of C6.
