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

Abstract

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.

• Authors: K Tanabe, Y Maeshima, K Ichinose, H Kitayama, Y Takazawa, K Hirokoshi, M Kinomura, H Sugiyama, H Makino
• Journal: Kidney international (Kidney Int) Vol. 71 Issue 3 Pg. 227-38 (Feb 2007) ISSN: 0085-2538 [Print] United States
• PMID: 17191085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Angiogenesis Inhibitors
• Collagen Type III
• Endostatins
• Integrin alpha6beta1
• Peptide Fragments
• Platelet Endothelial Cell Adhesion Molecule-1
• Transforming Growth Factor beta
• Vascular Endothelial Growth Factor A

Topics

• Actins (analysis)
• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Cell Proliferation (drug effects)
• Collagen Type III (analysis)
• Disease Progression
• Endostatins (analysis, pharmacology, therapeutic use)
• Immunoblotting
• Immunohistochemistry
• Integrin alpha6beta1 (analysis)
• Macrophages (drug effects)
• Male
• Mice
• Mice, Inbred ICR
• Monocytes (drug effects)
• Neovascularization, Pathologic (prevention & control)
• Peptide Fragments (pharmacology, therapeutic use)
• Peritoneum (blood supply, chemistry, pathology)
• Platelet Endothelial Cell Adhesion Molecule-1 (analysis)
• Sclerosis
• Transforming Growth Factor beta (analysis)
• Vascular Endothelial Growth Factor A (analysis)