NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy
NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy
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NOD2 通过加剧糖尿病肾病的炎症和足细胞胰岛素抵抗来促进肾损伤。
DOI：
10.1038/ki.2013.113
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发表时间：
2013-08-01
影响因子：
19.6
通讯作者：
Yi, Fan
中科院分区：
文献类型：
--
作者：
Du, Pengchao;Fan, Baoxia;Yi, Fan
越来越多的临床和动物模型研究表明，先天免疫系统和炎症机制的激活在糖尿病肾病的发病机制中发挥着重要作用。含有核苷酸结合寡聚化结构域 2 (NOD2) 是 NOD 样受体家族的成员，在先天免疫反应中发挥着重要作用。在这里，我们探讨了 NOD2 对糖尿病肾病发病机制的贡献，发现它在糖尿病患者和高脂饮食/链脲佐菌素诱导的糖尿病小鼠的肾活检中上调。此外，NOD2 缺乏可改善糖尿病小鼠的肾损伤。在体外，NOD2 诱导促炎反应并损害足细胞中的胰岛素信号传导和胰岛素诱导的葡萄糖摄取。此外，用高葡萄糖、晚期糖基化终产物、肿瘤坏死因子-α或转化生长因子-β（糖尿病肾病中常见的有害因素）处理的足细胞显着增加了NOD2表达。 NOD2 敲除糖尿病小鼠免受高血糖引起的去氧肾上腺素表达减少的影响。此外，NOD2表达的敲低在体外减弱了高血糖诱导的去氧肾上腺素下调，支持NOD2在介导高血糖诱导的足细胞功能障碍中的重要作用。因此，NOD2 是糖尿病肾病中将肾损伤与炎症和足细胞胰岛素抵抗联系起来的信号转导途径的关键成分之一。
An increasing number of clinical and animal model studies indicate that activation of the innate immune system and inflammatory mechanisms are important in the pathogenesis of diabetic nephropathy. Nucleotide-binding oligomerization domain containing 2 (NOD2), a member of the NOD-like receptor family, plays an important role in innate immune response. Here we explore the contribution of NOD2 to the pathogenesis of diabetic nephropathy and found that it was upregulated in kidney biopsies from diabetic patients and high-fat diet/streptozotocin–induced diabetic mice. Further, NOD2 deficiency ameliorated renal injury in diabetic mice.In vitro, NOD2 induced proinflammatory response and impaired insulin signaling and insulin-induced glucose uptake in podocytes. Moreover, podocytes treated with high glucose, advanced glycation end-products, tumor necrosis factor-α, or transforming growth factor-β (common detrimental factors in diabetic nephropathy) significantly increased NOD2 expression. NOD2 knockout diabetic mice were protected from the hyperglycemia-induced reduction in nephrin expression. Further, knockdown of NOD2 expression attenuated high glucose–induced nephrin downregulationin vitro, supporting an essential role of NOD2 in mediating hyperglycemia-induced podocyte dysfunction. Thus, NOD2 is one of the critical components of a signal transduction pathway that links renal injury to inflammation and podocyte insulin resistance in diabetic nephropathy.