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.

Abstract

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)-beta1, and chemokine monocyte chemoattractant protein-1 but not tumor necrosis factor-alpha 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-beta 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.

• Authors: Kunihiro Ichinose, Yohei Maeshima, Yoshihiko Yamamoto, Masaru Kinomura, Kumiko Hirokoshi, Hiroyuki Kitayama, Yuki Takazawa, Hitoshi Sugiyama, Yasushi Yamasaki, Naoki Agata, Hirofumi Makino
• Journal: Diabetes (Diabetes) Vol. 55 Issue 5 Pg. 1232-42 (May 2006) ISSN: 0012-1797 [Print] United States
• PMID: 16644677 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Ccl2 protein, mouse
• Chemokine CCL2
• Insulin
• Interleukin-6
• Isocoumarins
• Placebos
• Transforming Growth Factor beta
• isocoumarin NM-3

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Chemokine CCL2 (genetics)
• Diabetes Mellitus, Type 2 (complications, physiopathology)
• Diabetic Nephropathies (prevention & control)
• Heart (anatomy & histology)
• Insulin (blood)
• Interleukin-6 (genetics)
• Isocoumarins (therapeutic use)
• Kidney (anatomy & histology)
• Liver (anatomy & histology)
• Mice
• Obesity (complications, physiopathology)
• Organ Size
• Placebos
• Polymerase Chain Reaction
• Transforming Growth Factor beta (genetics)