3 years ago

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

Juan Wang, Xudong Xiang, Huiling Li, Zheng Dong, Shuangfa Qiu, Dongshan Zhang


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.

Publisher URL: https://www.nature.com/articles/cddis2017509

DOI: 10.1038/cddis.2017.509

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