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 4 mg/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-beta1, and alpha-smooth muscle actin was suppressed by endostatin peptide. Immunoreactivity for endogenous endostatin (whole molecule) and endostatin receptor alpha5beta1-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.
Tanabe
K
K
Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Maeshima
Y
Y
Ichinose
K
K
Kitayama
H
H
Takazawa
Y
Y
Hirokoshi
K
K
Kinomura
M
M
Sugiyama
H
H
Makino
H
H
D000199:Actins / Q000032:analysis; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D024061:Collagen Type III / Q000032:analysis; D018450:Disease Progression; D043169:Endostatins / Q000032:analysis / Q000494:pharmacology / Q000627:therapeutic use*; D015151:Immunoblotting; D007150:Immunohistochemistry; D039121:Integrin alpha6beta1 / Q000032:analysis; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009000:Monocytes / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D010537:Peritoneum / Q000098:blood supply* / Q000737:chemistry / Q000473:pathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D012598:Sclerosis; D016212:Transforming Growth Factor beta / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D000199:Actins; D020533:Angiogenesis Inhibitors; D024061:Collagen Type III; D043169:Endostatins; D039121:Integrin alpha6beta1; D010446:Peptide Fragments; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A