Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy.

Abstract

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.

• Authors: Yoshihiko Yamamoto, Yohei Maeshima, Hiroyuki Kitayama, Shinji Kitamura, Yuki Takazawa, Hitoshi Sugiyama, Yasushi Yamasaki, Hirofumi Makino
• Journal: Diabetes (Diabetes) Vol. 53 Issue 7 Pg. 1831-40 (Jul 2004) ISSN: 0012-1797 [Print] United States
• PMID: 15220208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Autoantigens
• Blood Glucose
• Collagen Type IV
• Membrane Proteins
• Platelet Endothelial Cell Adhesion Molecule-1
• Proteins
• RNA, Messenger
• nephrin
• type IV collagen alpha3 chain
• Creatinine

Topics

• Albuminuria (etiology)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Autoantigens (pharmacology)
• Blood Glucose (analysis)
• Collagen Type IV (metabolism, pharmacology)
• Creatinine (blood, metabolism)
• Diabetes Mellitus, Experimental (complications)
• Diabetic Neuropathies (blood, etiology, pathology, urine)
• Female
• Hypertrophy
• Kidney Glomerulus (drug effects, metabolism, pathology)
• Macrophages (pathology)
• Membrane Proteins
• Mice
• Mice, Inbred C57BL
• Monocytes (pathology)
• Neovascularization, Pathologic (metabolism)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• Proteins (genetics, metabolism)
• RNA, Messenger (metabolism)