CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice
CCR2 antagonism improves insulin resistance, lipid metabolism, and diabetic nephropathy in type 2 diabetic mice
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DOI：
10.1038/ki.2010.263
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发表时间：
2010-11-01
影响因子：
19.6
通讯作者：
Cha, Dae Ryong
中科院分区：
文献类型：
--
作者：
Kang, Young Sun;Lee, Mi Hwa;Cha, Dae Ryong
趋化因子配体 2 (CCL2) 与其受体 C-C 趋化因子受体 2 (CCR2) 结合，引发组织炎症，最近的研究表明，阻断该通路对糖尿病肾病具有有益作用。为了研究其保护机制，我们研究了 CCR2 拮抗剂 RS504393 对 db/db 小鼠胰岛素抵抗和糖尿病肾病的影响。多种生物标志物证实，施用这种拮抗剂可改善胰岛素抵抗，包括稳态模型评估指数水平、血浆胰岛素水平和脂质异常。用拮抗剂治疗的小鼠附睾脂肪量显着减少，脂肪细胞表型变化为小分化形式，CCL2 表达和脂质氢过氧化物水平降低。此外，CCR2拮抗剂治疗显着减少尿白蛋白排泄、系膜扩张，并抑制促纤维化和促炎细胞因子的合成。此外，CCR2拮抗剂改善了肾脏的脂质代谢、脂质过氧化氢、胆固醇和甘油三酯含量，并降低了尿8-异前列烷水平。因此，我们的研究结果表明，CCR2 拮抗剂可以通过调节脂肪组织改善胰岛素抵抗，并通过代谢和抗纤维化作用恢复 2 型糖尿病小鼠的肾功能。肾脏国际 (2010) 78, 883-894; doi：10.1038/ki.2010.263； 2010 年 8 月 4 日在线发布
Chemokine ligand 2 (CCL2) binds to its receptor C-C chemokine receptor 2 (CCR2), initiating tissue inflammation, and recent studies have suggested a beneficial effect of a blockade of this pathway in diabetic nephropathy. To investigate the mechanism of protection, we studied the effect of RS504393, a CCR2 antagonist, on insulin resistance and diabetic nephropathy in db/db mice. Administering this antagonist improved insulin resistance as confirmed by various biomarkers, including homeostasis model assessment index levels, plasma insulin levels, and lipid abnormalities. Mice treated with the antagonist had a significant decrease in epididymal fat mass as well as phenotypic changes of adipocytes into small differentiated forms with decreased CCL2 expression and lipid hydroperoxide levels. In addition, treatment with the CCR2 antagonist markedly decreased urinary albumin excretion, mesangial expansion, and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, the CCR2 antagonist improved lipid metabolism, lipid hydroperoxide, cholesterol, and triglyceride contents of the kidney, and decreased urinary 8-isoprostane levels. Hence, our findings suggest that CCR2 antagonists can improve insulin resistance by modulation of the adipose tissue and restore renal function through both metabolic and anti-fibrotic effects in type 2 diabetic mice. Kidney International (2010) 78, 883-894; doi:10.1038/ki.2010.263; published online 4 August 2010