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Abstract: SA-PO095

MeCP2 Promotes Cisplatin-Induced AKI Through Epigenetic Regulation of Irf8

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Tang, Hui, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei , China
  • Su, Hua, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei , China
  • Zhang, Chun, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei , China
Background

Emerging evidence suggests that epigenetic regulation like DNA methylation plays an important part in the process of acute kidney injury (AKI), but the mechanism remains largely elusive. Methyl-CpG binding protein 2 (MeCP2) is an epigenetic regulator which binds to methylated cytosines and functions as gene transcriptional inhibitor or activator. The role of MeCP2 was examined most notably in brain development, while the involvement of MeCP2 in renal disease remains unknown.

Methods

Twenty male C57 mice were randomly grouped into control, cisplatin-1d, cisplatin-2d, and cisplatin-4d according to the time of execution after cisplatin intraperitoneal injection. HK-2 cells were exposed to cisplatin at 20uM for variable incubation time. HK-2 cells were transfected by siRNA to knockdown MeCP2 expression. Apoptosis was detected with the TUNEL method. Chromatin immunoprecipitation assay (CHIP) was used to analyze the binding of MeCP2 to the interferon regulatory factor 8 (Irf8) gene.

Results

We found consistent expression of MeCP2 in renal cortical tubules of SD rat, WKY rat, and C57 mouse. Compared with the sham group, cisplatin-treated mice kidney showed significant upregulation of MeCP2 in proximal tubules in both protein and mRNA level, accompanied by severe renal histology changes and the upregulation of NGAL and KIM-1. In vitro, MeCP2 was also induced in cultured proximal tubular cells by cisplatin treatment. Interestingly, knocking down MeCP2 alleviated caspase-3-dependent tubular cell apoptosis but enhanced cell autophagy induced by cisplatin. Furthermore, a pro-apoptotic gene interferon regulatory factor 8 (Irf8) was found upregulated in tubular cells by cisplatin in vivo and in vitro. Importantly, we demonstrated that MeCP2 upregulated Irf8 expression by directly binding to its gene.

Conclusion

Elevated expression of MeCP2 was found in cisplatin-treated renal proximal tubules in vivo and in vitro. MeCP2 promoted cisplatin-induced renal tubular damage by facilitating apoptotic process and inhibiting autophagy activity. The epigenetic regulation of pro-apoptotic gene Irf8 by MeCP2 may be the possible mechanism implicated in the pathophysiological process of cisplatin-induced AKI.

Funding

  • Government Support - Non-U.S.