miR-218 regulates diabetic nephropathy via targeting IKK-β and modulating NK-κB-mediated inflammation
miR-218 regulates diabetic nephropathy via targeting IKK-β and modulating NK-κB-mediated inflammation
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DOI：
10.1002/jcp.29224
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发表时间：
2019-09-24
影响因子：
5.6
通讯作者：
Zhang, Xuan
中科院分区：
文献类型：
--
作者：
Li, Mo;Guo, Qiushi;Zhang, Xuan
糖尿病肾病（DN）是糖尿病常见的临床相关并发症，与毛细血管损伤有关，但这种疾病的病因尚不清楚。核因子-κ B（NF-κ B）活化与DN相关炎症和疾病进展相关。最近的研究表明microRNA是DN进展的诊断性生物标志物，与DN进展中的炎症相关。已知miR-218在人类某些癌症中发挥关键调节作用，但其对DN病理学的影响仍不确定。因此，本研究试图评估miR-218如何影响糖尿病肾病大鼠链脲佐菌素诱导模型和体外模型系统中的疾病进展，在体外模型系统中，小鼠足细胞被高葡萄糖水平刺激。我们发现miR-218在两个模型系统中相对于适当的对照组显著下调，并且这种下调与IKK-β上调相关。在DN大鼠模型中，过表达miR-218足以减轻肾损伤。我们进一步确定，足细胞增殖明显受损葡萄糖治疗，导致这些细胞的凋亡死亡，和miR-218模拟物能够减少这些表型。过表达miR-218还显著抑制了该模型系统中的炎症反应，如肿瘤坏死因子-α、白细胞介素-6（IL-6）、IL-1 β和MCP-1水平降低所证明的。然后，我们使用双荧光素酶报告基因测定证实miR-218靶向编码IKK-β的信使RNA。总之，我们的研究结果提供了明确的证据表明，miR-218调节NF-κ B介导的炎症，这是DN进展的核心。
Diabetic nephropathy (DN) is a common clinically relevant complication of diabetes that is associated with damage to the capillaries, yet the etiology of this condition remains unclear. Nuclear factor-kappa B (NF-kappa B) activation is known to be associated with DN-related inflammation and disease progression. Recent work indicated that microRNAs are diagnostic biomarkers of DN progression associated with inflammation in the progression of DN. miR-218 is known to play key regulatory roles in certain cancers in humans, while its influence on DN pathology remains uncertain. The present study, therefore, sought to assess how miR-218 influences the progression of disease in both a rat streptozotocin-induced model of DN and as well as an in vitro model system in which mouse podocytes were stimulated with high glucose levels. We found miR-218 to be markedly downregulated in both model systems relative to appropriate controls, and this downregulation was associated with IKK-beta upregulation. In DN rat model, overexpressing miR-218 was sufficient to reduce renal injury. We further determined that podocyte proliferation was markedly impaired by glucose treatment, leading to the apoptotic death of these cells, and miR-218 mimics were able to reduce these phenotypes. Overexpressing miR-218 also significantly dampened inflammatory responses in this model system, as evidenced by reduced tumor necrosis factor-alpha, interleukin-6 (IL-6), IL-1 beta, and MCP-1 levels. We then confirmed that miR-218 targeting the messenger RNA encoding IKK-beta using a dual-luciferase reporter assay. Together, our results provide clear evidence that miR-218 regulate NF-kappa B-mediated inflammation, which is central to DN progression.