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Diabetes 54:2891-2903, 2005
© 2005 by the American Diabetes Association, Inc.

Antiangiogenic Endostatin Peptide Ameliorates Renal Alterations in the Early Stage of a Type 1 Diabetic Nephropathy Model

Kunihiro Ichinose1, Yohei Maeshima1, Yoshihiko Yamamoto1, Hiroyuki Kitayama1, Yuki Takazawa1, Kumiko Hirokoshi1, Hitoshi Sugiyama1, Yasushi Yamasaki1, Katsumi Eguchi2, and Hirofumi Makino1

1 Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
2 First Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Diabetic nephropathy is one of the major microvascular complications in diabetes and is the leading cause of end-stage renal disease worldwide. Among various factors, angiogenesis-associated factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2 are involved in the development of diabetic nephropathy. We previously reported the therapeutic efficacy of antiangiogenic tumstatin peptide in the early diabetic nephropathy model. Here, we examine the effect of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in preventing progression in the type 1 diabetic nephropathy mouse model. Endostatin peptide did not affect hyperglycemia induced by streptozotocin (STZ). Glomerular hypertrophy, hyperfiltration, and albuminuria were significantly suppressed by endostatin peptide (5 mg/kg) in STZ-induced diabetic mice. Glomerular mesangial matrix expansion, the increase of glomerular type IV collagen, endothelial area (CD31+), and F4/80+ monocyte/macrophage accumulation were significantly inhibited by endostatin peptide. Increase in the renal expression of VEGF-A, flk-1, Ang-2, an antagonist of angiopoietin-1, transforming growth factor-ß1, interleukin-6, and monocyte chemoattractant protein-1 was inhibited by endostatin peptide in diabetic mice. Decrease of nephrin mRNA and protein in diabetic mice was suppressed by treatment with endostatin peptide. The level of endostatin in the renal cortex and sera was increased in diabetic mice. Endogenous renal levels of endostatin were decreased in endostatin peptide–treated groups in parallel with VEGF-A. Although serum levels of endostatin were decreased in the low-dose endostatin-peptide group, high-dose administration resulted in elevated serum levels of endostatin. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in diabetic nephropathy.

Address correspondence and reprint requests to Dr. Yohei Maeshima, Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. E-mail: ymaeshim{at}md.okayama-u.ac.jp

Abbreviations: Ang, angiopoietin; CCr, creatinine clearance; ELISA, enzyme-linked immunosorbent assay; ESRD, end-stage renal disease; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; NC1, noncollagenous domain 1; STZ, streptozotocin; TGF, transforming growth factor; UACR, urinary albumin-to-creatinine ratio; VEGF vascular endothelial growth factor


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.