MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI.
MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI.
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万古霉素诱导的 AKI 期间 MBD2 上调 miR-301a-5p 诱导肾细胞凋亡
DOI：
10.1038/cddis.2017.509
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发表时间：
2017-10-12
影响因子：
9
通讯作者：
Zhang D
中科院分区：
文献类型：
--
作者：
Wang J;Li H;Qiu S;Dong Z;Xiang X;Zhang D
尽管DNA甲基化发生在急性肾损伤（阿基）中，但它如何影响阿基的进展仍不清楚。甲基化CpG结合域蛋白2（MBD 2）是甲基化的蛋白质阅读器，用于分析DNA甲基化对万古霉素（货车）诱导的阿基的影响。在这里，在培养的人肾小管上皮细胞（HK-2），我们表明，敲低MBD 2的siRNA衰减VAN诱导的细胞凋亡，caspase活性，BAX和裂解caspase 3的表达。有趣的是，通过siRNA敲减MBD 2与miR-301 a-5 p的抑制有关。机制研究证实，MBD 2与miR-301 a-5 p启动子的这些甲基化CpG元件结合，然后通过抑制甲基化来激活miR-301 a-5 p启动子。此外，anti-miR-301 a-5 p可显著阻断VAN诱导的HK-2细胞凋亡和caspase活性，同时下调p53，上调MITF、HDGF和MDM-4的表达。后者基因被进一步鉴定为miR-301 a-5 p的靶基因，并且MDM-4的沉默促进p53积累。在体内，MBD 2基因敲除小鼠（MBD 2-KO）对VAN诱导的阿基具有抵消作用，这通过肾功能、组织学、细胞凋亡和炎症的分析来指示。MBD 2-KO还显著抑制miR-301 a-5 p、p53、BAX和切割的caspase 3的表达，并恢复MDM-4、MITF和HDGF的表达。最后，体内抑制miR-301 a-5 p也改善了VAN诱导的阿基。总之，这些结果显示了VAN诱导的阿基中的新型MBD 2/miR-301 a-5 p/MITF、HDGF和MDM-4/p53通路。
Despite DNA methylation occurred in acute kidney injury (AKI), how it influenced progression of AKI remains unclear. Methyl-CpG-binding domain protein 2 (MBD2), a protein readers of methylation, was used to analyze the impact of DNA methylation on vancomycin (VAN)-induced AKI. Here, in cultured human kidney tubular epithelial cells (HK-2), we show that knockdown of MBD2 by siRNA attenuated VAN-induced apoptosis, caspase activity, and the expression of BAX and cleaved caspase 3. Interestingly, knockdown of MBD2 by siRNA was associated with the suppression of miR-301a-5p. Mechanistic studies confirmed MBD2 binds to these methylated CpG elements of miR-301a-5p promoter, and then activates miR-301a-5p promoter by suppressing methylation. Furthermore, anti-miR-301a-5p significantly blocked VAN-induced apoptosis and caspase activity in HK-2 cells, which was accompanied by downregulation of p53, and upregulation of MITF, HDGF and MDM-4 together. The latter genes were further identified as target genes of miR-301a-5p, and silencing of MDM-4 promoted p53 accumulation. In vivo, mice with MBD2 knockout (MBD2-KO) were counteracted to VAN-induced AKI, indicated by the analysis of renal function, histology, apoptosis and inflammation. MBD2-KO also significantly suppressed the expression of miR-301a-5p, p53, BAX and cleaved caspase 3, and restored the expression of MDM-4, MITF and HDGF. Finally, in vivo inhibition of miR-301a-5p also ameliorated VAN-induced AKI. Together, these results show the novel MBD2/miR-301a-5p/MITF, HDGF and MDM-4/p53 pathway in VAN-induced AKI.
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影响因子：
1.5
作者：
Hanrahan, T. P.;Kotapati, C.;Udy, A.
通讯作者：
Udy, A.
影响因子：
3.5
作者：
Niu, Xuemin;Fu, Na;Nan, Yuemin
通讯作者：
Nan, Yuemin
影响因子：
3.7
作者：
Bian C;Xu T;Zhu H;Pan D;Liu Y;Luo Y;Wu P;Li D
通讯作者：
Li D
影响因子：
--
作者：
Humanes B;Jado JC;Camaño S;López-Parra V;Torres AM;Álvarez-Sala LA;Cercenado E;Tejedor A;Lázaro A
通讯作者：
Lázaro A
影响因子：
3.3
作者：
Nishino, Y;Takemura, S;Kinoshita, H
通讯作者：
Kinoshita, H