DNA methylation protects against cisplatin-induced kidney injury by regulating specific genes, including interferon regulatory factor 8

Chunyuan Guo, Lirong Pei, Xiao Xiao, QingQing Wei, Jiankang Chen, Hanfei Ding, Shuang Huang, Guoping Fan, Huidong Shi, Zheng Dong

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

DNA methylation is an epigenetic mechanism that regulates gene transcription without changing primary nucleotide sequences. In mammals, DNA methylation involves the covalent addition of a methyl group to the 5-carbon position of cytosine by DNA methyltransferases (DNMTs). The change of DNA methylation and its pathological role in acute kidney injury (AKI) remain largely unknown. Here, we analyzed genome-wide DNA methylation during cisplatin-induced AKI by reduced representation bisulfite sequencing. This technique identified 215 differentially methylated regions between the kidneys of control and cisplatin-treated animals. While most of the differentially methylated regions were in the intergenic, intronic, and coding DNA sequences, some were located in the promoter or promoter-regulatory regions of 15 protein-coding genes. To determine the pathological role of DNA methylation, we initially examined the effects of the DNA methylation inhibitor 5-aza-2'-deoxycytidine and showed it increased cisplatin-induced apoptosis in a rat kidney proximal tubular cell line. We further established a kidney proximal tubule-specific DNMT1 (PT-DNMT1) knockout mouse model, which showed more severe AKI during cisplatin treatment than wild-type mice. Finally, interferon regulatory factor 8 (Irf8), a pro-apoptotic factor, was identified as a hypomethylated gene in cisplatin-induced AKI, and this hypomethylation was associated with a marked induction of Irf8. In the rat kidney proximal tubular cells, the knockdown of Irf8 suppressed cisplatin-induced apoptosis, supporting a pro-death role of Irf8 in renal tubular cells. Thus, DNA methylation plays a protective role in cisplatin-induced AKI by regulating specific genes, such as Irf8.

Original languageEnglish (US)
Pages (from-to)1194-1205
Number of pages12
JournalKidney International
Volume92
Issue number5
DOIs
StatePublished - Nov 2017

Keywords

  • DNA methylation
  • DNA methyltransferases
  • acute kidney injury
  • cisplatin
  • nephrotoxicity

ASJC Scopus subject areas

  • Nephrology

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