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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.
AuthorsK Tanabe, Y Maeshima, K Ichinose, H Kitayama, Y Takazawa, K Hirokoshi, M Kinomura, H Sugiyama, H Makino
JournalKidney international (Kidney Int) Vol. 71 Issue 3 Pg. 227-38 (Feb 2007) ISSN: 0085-2538 [Print] United States
PMID17191085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Actins
  • Angiogenesis Inhibitors
  • Antigens, CD31
  • Collagen Type III
  • Endostatins
  • Integrin alpha6beta1
  • Peptide Fragments
  • Transforming Growth Factor beta
  • Vascular Endothelial Growth Factor A
Topics
  • Actins (analysis)
  • Angiogenesis Inhibitors (therapeutic use)
  • Animals
  • Antigens, CD31 (analysis)
  • 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)
  • Sclerosis
  • Transforming Growth Factor beta (analysis)
  • Vascular Endothelial Growth Factor A (analysis)

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