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Diabetes 53:1831-1840, 2004
© 2004 by the American Diabetes Association, Inc.

Tumstatin Peptide, an Inhibitor of Angiogenesis, Prevents Glomerular Hypertrophy in the Early Stage of Diabetic Nephropathy

Yoshihiko Yamamoto, Yohei Maeshima, Hiroyuki Kitayama, Shinji Kitamura, Yuki Takazawa, Hitoshi Sugiyama, Yasushi Yamasaki, and Hirofumi Makino

Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

In the early stage of diabetic nephropathy (one of the major microvascular complications of diabetes) glomerular hyperfiltration and hypertrophy are observed. It is clinically important to regulate glomerular hypertrophy for preventing glomerulosclerosis. The number of glomerular endothelial cells is known to be increased in diabetic nephropathy associated with enlarged glomerular tufts, suggesting that the mechanism is similar to that of angiogenesis. Tumstatin peptide is an angiogenesis inhibitor derived from type IV collagen and inhibits in vivo neovascularization induced by vascular endothelial growth factor (VEGF), one of the mediators of glomerular hypertrophy in diabetic nephropathy. Here, we show the effect of tumstatin peptide in inhibiting alterations in early diabetic nephropathy. Glomerular hypertrophy, hyperfiltration, and albuminuria were suppressed by tumstatin peptide (1 mg/kg) in streptozotocin-induced diabetic mice. Glomerular matrix expansion, the increase of total glomerular cell number and glomerular endothelial cells (CD31 positive), and monocyte/macrophage accumulation was inhibited by tumstatin peptide. Increase in renal expression of VEGF, flk-1, and angiopoietin-2, an antagonist of angiopoietin-1, was inhibited by tumstatin treatment in diabetic mice. Alteration of glomerular nephrin expression, a podocyte protein crucial for maintaining glomerular filtration barrier, was recovered by tumstatin in diabetic mice. Taken together, these results demonstrate the potential use of antiangiogenic tumstatin peptide as a novel therapeutic agent in early diabetic nephropathy.

Address correspondence and reprint requests to Dr. Yohei Maeshima, Assistant Professor of Medicine, 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; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PAS, periodic acid-Schiff; PI, phosphatidylinositol; 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 © 2004 by the American Diabetes Association.