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
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
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DOI：
10.2337/db05-1367
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发表时间：
2006-05-01
期刊：
影响因子：
7.7
通讯作者：
Makino, H
中科院分区：
文献类型：
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作者：
Ichinose, K;Maeshima, Y;Makino, H
糖尿病肾病是终末期肾衰竭的最常见原因，其进展的机制之一是与血管生成因子如血管内皮生长因子（VEGF）-A和血管生成素（Ang）-2（Ang-1的拮抗剂）的增加相关的血管生成现象。在本研究中，我们检查了2-（8-羟基-6-甲氧基-1-氧代-1H-2-苯并吡喃-3-基）丙酸（NM-3），一种小分子异香豆素具有抗血管生成活性，使用糖尿病db/db小鼠，肥胖2型糖尿病模型的治疗效果。在对照db/db小鼠中观察到的肾重量、肾小球体积、肌酐清除率、尿白蛋白排泄、总系膜分数、肾小球IV型胶原、肾小球内皮面积（CD 31（+））和单核细胞/巨噬细胞积聚（F4/80（+））的增加通过每天腹膜内注射NM-3（100 mg/kg，持续8周）而被显著抑制。在db/db小鼠中，NM-3还抑制VEGF-A、Ang-2、纤维形成因子转化生长因子（TGF）-β 1和趋化因子单核细胞趋化蛋白-1（但不抑制肿瘤坏死因子-α）的肾脏表达增加。此外，NM-3可恢复db/db小鼠nephrin mRNA和蛋白水平的降低。此外，用NM-3治疗db/db小鼠并不影响体重、血糖、血清胰岛素或摄食量。NM-3能显著抑制高糖诱导的足细胞VEGF表达的增加，也能显著抑制高糖诱导的系膜细胞VEGF和TGF-β表达的增加。总之，这些结果表明NM-3作为2型糖尿病肾脏改变的新型治疗剂的潜在用途。
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)-beta 1, 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.