Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice
Blockade of CCL2/CCR2 signalling ameliorates diabetic nephropathy in db/db mice
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DOI：
10.1093/ndt/gfs555
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发表时间：
2013-07-01
影响因子：
6.1
通讯作者：
Chung, Choon Hee
中科院分区：
文献类型：
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作者：
Seok, Su Jin;Lee, Eun Soo;Chung, Choon Hee
背景CCL 2/C-C趋化因子受体2（CCR 2）信号转导在包括糖尿病肾病在内的各种肾脏疾病中发挥重要作用。我们在2型糖尿病小鼠模型中研究了CCR 2拮抗剂RS 102895对糖尿病肾病发展的肾保护作用。对6周龄糖尿病db/db和非糖尿病db/m小鼠饲喂正常饲料或与2 mg/kg/天RS 102895混合的饲料，持续9周。我们研究了CCR 2拮抗剂对血糖、血压、蛋白尿以及肾脏结构和超微结构的影响。经CCR 2拮抗剂治疗后，糖尿病诱导的白蛋白尿显着改善，RS 102895治疗的糖尿病小鼠的葡萄糖不耐受也得到改善。RS 102895不影响血压、体重或肾脏重量。RS 102895治疗后，糖尿病肾脏的系膜扩张、肾小球基底膜增厚和结蛋白染色增加显著改善。在RS 102895处理的糖尿病小鼠肾脏中，血管内皮生长因子mRNA表达的上调和nephrin mRNA表达的下调显著改善。RS 102895治疗可有效减弱糖尿病患者肾脏CD 68和肌酐酶II以及尿丙二醛的升高。通过RS 102895阻断CCL 2/CCR 2信号传导不仅通过改善血糖水平，而且通过阻断2型糖尿病小鼠中的巨噬细胞浸润、炎症和氧化应激，阻止CCL 2/CCR 2信号传导改变肾肾蛋白和VEGF表达，从而改善糖尿病肾病。
Background. CCL2/C-C chemokine receptor 2 (CCR2) signalling is suggested to play a significant role in various kidney diseases including diabetic nephropathy. We investigated the renoprotective effect of a CCR2 antagonist, RS102895, on the development of diabetic nephropathy in a type 2 diabetic mouse model.Methods. Six-week-old diabetic db/db and non-diabetic db/m mice were fed either normal chow or chow mixed with 2 mg/kg/day of RS102895 for 9 weeks. We investigated the effects of CCR2 antagonism on blood glucose, blood pressure, albuminuria and the structure and ultrastructure of the kidney.Results. Diabetes-induced albuminuria was significantly improved after CCR2 antagonist treatment, and glucose intolerance was improved in the RS102895-treated diabetic mice. RS102895 did not affect blood pressure, body weight or kidney weight. Mesangial expansion, glomerular basement membrane thickening and increased desmin staining in the diabetic kidney were significantly improved after RS102895 treatment. The up-regulation of vascular endothelial growth factor mRNA expression and the down-regulation of nephrin mRNA expression were markedly improved in the kidneys of RS102895-treated diabetic mice. Increased renal CD68 and arginase II and urinary malondialdehyde in diabetes were effectively attenuated by RS102895 treatment.Conclusion. Blockade of CCL2/CCR2 signalling by RS102895 ameliorates diabetic nephropathy not only by improving blood glucose levels but also by preventing CCL2/CCR2 signalling from altering renal nephrin and VEGF expressions through blocking macrophage infiltration, inflammation and oxidative stress in type 2 diabetic mice.