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.
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.
Ichinose
Kunihiro
K
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.
Maeshima
Yohei
Y
Yamamoto
Yoshihiko
Y
Kinomura
Masaru
M
Hirokoshi
Kumiko
K
Kitayama
Hiroyuki
H
Takazawa
Yuki
Y
Sugiyama
Hitoshi
H
Yamasaki
Yasushi
Y
Agata
Naoki
N
Makino
Hirofumi
H
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D006321:Heart / Q000033:anatomy & histology; D007328:Insulin / Q000097:blood; D015850:Interleukin-6 / Q000235:genetics; D049934:Isocoumarins / Q000627:therapeutic use*; D007668:Kidney / Q000033:anatomy & histology; D008099:Liver / Q000033:anatomy & histology; D051379:Mice; D009765:Obesity / Q000150:complications / Q000503:physiopathology*; D009929:Organ Size; D010919:Placebos; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000235:genetics
D020533:Angiogenesis Inhibitors; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D007328:Insulin; D015850:Interleukin-6; D049934:Isocoumarins; D010919:Placebos; D016212:Transforming Growth Factor beta; C453300:isocoumarin NM-3