DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury.
DNA methyltransferase 1 may be a therapy target for attenuating diabetic nephropathy and podocyte injury.
复制标题
DNA甲基转移酶1可能是减轻糖尿病肾病和足细胞损伤的治疗靶点。
DOI：
10.1016/j.kint.2017.01.010
复制
发表时间：
2017-07
影响因子：
19.6
通讯作者：
Li Zhang;Qianmei Zhang;Shuangxin Liu;Yuan-han Chen;Rui-zhao Li;Ting Lin;Chunping Yu;Hong Zhang-Hong-Zha
中科院分区：
文献类型：
--
作者：
Li Zhang;Qianmei Zhang;Shuangxin Liu;Yuan-han Chen;Rui-zhao Li;Ting Lin;Chunping Yu;Hong Zhang-Hong-Zha
DNA甲基化在糖尿病肾病中的作用，特别是对足细胞完整性的影响尚不清楚。在此，我们发现db/db小鼠模型中的白蛋白尿在用DNA甲基化抑制剂治疗后显著减弱。这伴随着肾小球肥大、系膜基质扩张和足细胞损伤的减轻。在糖尿病状态下，足细胞DNA甲基转移酶1（Dnmt 1）、核因子Sp1和核因子κ B（NFκB）-p65在体内和体外的表达均明显增加。用5-氮杂胞苷或5-氮杂-2 '-脱氧胞苷或Dnmt 1敲低处理后，Dnmt 1表达的增加减弱，伴随着由高甲基化引起的足细胞裂膜蛋白的恢复和足细胞运动性的改善。进一步的研究发现，高糖培养足细胞核内Sp1与NFκB-p65相互作用，Sp1与Dnmt 1启动子区结合。通过观察到使用光辉霉素A或siRNA敲低Sp1可降低Dnmt 1蛋白水平，证实了Sp1/NFκB-p65复合物参与Dnmt 1调节。荧光素酶报告基因检测进一步表明Dnmt 1是Sp1的直接靶点。因此，抑制DNA甲基化可能是治疗糖尿病肾病的一个新的治疗途径。因此，Sp1/NFκB p65-Dnmt 1通路可能成为糖尿病肾病足细胞损伤的治疗靶点。
The contribution of DNA methylation to diabetic nephropathy, especially the effect on podocyte integrity, is not clarified. Here we found that albuminuria in a db/db mouse model was markedly attenuated after treatment with a DNA methylation inhibitor. This was accompanied by alleviation of glomerular hypertrophy, mesangial matrix expansion, and podocyte injury. The expression of DNA methyltransferase 1 (Dnmt1), nuclear factor Sp1, and nuclear factor kappa B (NFκB)-p65 markedly increased in podocytesin vivoandin vitrounder the diabetic state. The increased expression of Dnmt1 was attenuated after treatment with 5-azacytidine or 5-aza-2'-deoxycytidine or Dnmt1 knockdown, accompanied by restored decreased podocyte slit diaphragm proteins resulting from hypermethylation and improved podocyte motility. Further studies found that increased Sp1 and NFκB-p65 interacted in the nucleus of podocytes incubated with high glucose, and Sp1 bound to the Dnmt1 promoter region. The involvement of the Sp1/NFκB-p65 complex in Dnmt1 regulation was confirmed by the observation that Sp1 knockdown using mithramycin A or siRNA decreased Dnmt1 protein levels. The luciferase reporter assay further indicated that Dnmt1 was a direct target of Sp1. Thus, inhibition of DNA methylation may be a new therapeutic avenue for treating diabetic nephropathy. Hence, the Sp1/NFκB p65-Dnmt1 pathway may be exploited as a therapeutic target for protecting against podocyte injury in diabetic nephropathy.