MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI
| Autor: | Juan Wang, Huiling Li, Zheng Dong, Xudong Xiang, Shuangfa Qiu, Dongshan Zhang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Cancer Research Apoptosis Cell Cycle Proteins Kidney Mice 0302 clinical medicine RNA Small Interfering Promoter Regions Genetic Cell Line Transformed bcl-2-Associated X Protein Regulation of gene expression Mice Knockout Gene knockdown Caspase 3 Intracellular Signaling Peptides and Proteins Nuclear Proteins Methylation Acute Kidney Injury DNA-Binding Proteins 030220 oncology & carcinogenesis DNA methylation Original Article RNA Interference Immunology Biology 03 medical and health sciences Cellular and Molecular Neuroscience Bcl-2-associated X protein Downregulation and upregulation Vancomycin Proto-Oncogene Proteins In Situ Nick-End Labeling Animals Humans Microphthalmia-Associated Transcription Factor Kidney metabolism Cell Biology DNA Methylation Molecular biology Mice Inbred C57BL Cytoskeletal Proteins MicroRNAs 030104 developmental biology Gene Expression Regulation Cancer research biology.protein CpG Islands Tumor Suppressor Protein p53 |
| Zdroj: | Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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