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2-(8-Hydroxy-6-Methoxy-1-Oxo-1H-2-Benzopyran-3-yl) Propionic Acid, an Inhibitor of Angiogenesis, Ameliorates Renal Alterations in Obese Type 2 Diabetic Mice

¹ Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
² Department of Medicine and Clinical Science, Genzyme, Framingham, Massachusetts

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, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. E-mail: ymaeshim{at}md.okayama-u.ac.jp

Abbreviations: Ang, angiopoietin; CCr, creatinine clearance; ESRD, end-stage renal disease; GBM, glomerular basement membrane; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; NM-3, 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid; TGF, transforming growth factor; TNF-, tumor necrosis factor-; UACR, urinary albumin-to-creatinine ratio; VEGF, vascular endothelial growth factor

One of the mechanisms involved in the progression of diabetic nephropathy, the most common cause of end-stage renal failure, is angiogenic phenomenon associated with the increase of angiogenic factors such as vascular endothelial growth factor (VEGF)-A and angiopoietin (Ang)-2, an antagonist of Ang-1. In the present study, we examined the therapeutic efficacy of 2-(8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl) propionic acid (NM-3), a small molecule isocoumarin with antiangiogenic activity, using diabetic db/db mice, a model of obese type 2 diabetes. Increases in kidney weight, glomerular volume, creatinine clearance, urinary albumin excretion, total mesangial fraction, glomerular type IV collagen, glomerular endothelial area (CD31⁺), and monocyte/macrophage accumulation (F4/80⁺) observed in control db/db mice were significantly suppressed by daily intraperitoneal injection of NM-3 (100 mg/kg, for 8 weeks). Increases in renal expression of VEGF-A, Ang-2, fibrogenic factor transforming growth factor (TGF)-ß1, and chemokine monocyte chemoattractant protein-1 but not tumor necrosis factor- were also inhibited by NM-3 in db/db mice. Furthermore, decreases of nephrin mRNA and protein levels in db/db mice were recovered by NM-3. In addition, treatment of db/db mice with NM-3 did not affect body weight, blood glucose, serum insulin, or food consumption. NM-3 significantly suppressed the increase of VEGF induced by high glucose in cultured podocytes and also suppressed the increase of VEGF and TGF-ß induced by high glucose in cultured mesangial cells. Taken together, these results demonstrate the potential use of NM-3 as a novel therapeutic agent for renal alterations in type 2 diabetes.

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