Endostatin peptide, an inhibitor of angiogenesis, prevents the progression of peritoneal sclerosis in a mouse experimental model

Peritoneal sclerosis is a major and serious complication in patients on long-term continuous ambulatory peritoneal dialysis ( PD). The involvement of angiogenesis and proangiogenic factors such as vascular endothelial growth factor ( VEGF)-A in progressing peritoneal sclerosis has been reported. We previously reported the therapeutic efficacy of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in a mouse diabetic nephropathy model. Here, we examined the therapeutic effect of endostatin peptide in preventing progression in a mouse peritoneal sclerosis model. Male ICR mice received intraperitoneal injections of chlorhexidine gluconate ( CG) every other day to induce peritoneal sclerosis. Endostatin peptide ( 1 or 4mg/kg/day) was administered via subcutaneously implanted osmotic minipumps. Peritoneal sclerosis ( day 24) was significantly suppressed by endostatin peptide in a dose-dependent manner. Peritoneal accumulation of type III collagen was significantly suppressed by endostatin peptide. Increase in the number of CD31( +) blood vessels, F4/80( +) monocyte/macrophage accumulation, and 5-bromodeoxyuridine(+) proliferating cells was significantly inhibited by endostatin peptide. Increase in peritoneal expression of VEGF-A, profibrotic transforming growth factor-beta 1, and alpha-smooth muscle actin was suppressed by endostatin peptide. Immunoreactivity for endogenous endostatin ( whole molecule) and endostatin receptor alpha 5 beta 1-integrin was increased and colocalized to CD31( +) blood vessels in the thickened peritonea of CG-injected mice. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in preventing peritoneal sclerosis, a severe complication in patients undergoing long-term PD.