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MBD2 通过上调 miR-301a-5p 诱导万古霉素诱导的 AKI 期间的肾细胞凋亡。

MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI.

机构信息

Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Emergency Medicine and Difficult Diseases Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

出版信息

Cell Death Dis. 2017 Oct 12;8(10):e3120. doi: 10.1038/cddis.2017.509.

DOI:10.1038/cddis.2017.509
PMID:29022913
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5682674/
Abstract

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.

摘要

尽管 DNA 甲基化发生在急性肾损伤 (AKI) 中，但它如何影响 AKI 的进展尚不清楚。甲基化结合域蛋白 2 (MBD2) 是一种 DNA 甲基化的“读码器”蛋白，我们利用其分析 DNA 甲基化对万古霉素 (VAN) 诱导的 AKI 的影响。在体外培养的人肾小管上皮细胞 (HK-2) 中，我们发现 siRNA 敲低 MBD2 可减弱 VAN 诱导的细胞凋亡、半胱氨酸天冬氨酸蛋白酶 (caspase) 活性以及 Bax 和 cleaved caspase 3 的表达。有趣的是，siRNA 敲低 MBD2 与 miR-301a-5p 的抑制有关。机制研究证实 MBD2 与 miR-301a-5p 启动子上这些甲基化的 CpG 元件结合，并通过抑制甲基化来激活 miR-301a-5p 启动子。此外，抗 miR-301a-5p 显著阻断了 VAN 诱导的 HK-2 细胞凋亡和 caspase 活性，同时下调了 p53，上调了 MITF、HDGF 和 MDM-4。进一步确定了后三种基因是 miR-301a-5p 的靶基因，沉默 MDM-4 促进了 p53 的积累。在体内，MBD2 敲除 (MBD2-KO) 小鼠对抗 VAN 诱导的 AKI，通过肾功能、组织学、凋亡和炎症分析表明。MBD2-KO 还显著抑制了 miR-301a-5p、p53、Bax 和 cleaved caspase 3 的表达，并恢复了 MDM-4、MITF 和 HDGF 的表达。最后，体内抑制 miR-301a-5p 也改善了 VAN 诱导的 AKI。综上所述，这些结果表明了 MBD2/miR-301a-5p/MITF、HDGF 和 MDM-4/p53 通路在 VAN 诱导的 AKI 中的新作用。

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