MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis

Yuxin Xie, Bohao Liu, Jian Pan, Jiamiao Liu, Xiaozhou Li, Huiling Li, Shuangfa Qiu, Xudong Xiang, Peiling Zheng, Junxiang Chen, Yunchang Yuan, Zheng Dong, Dongshan Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Our previous study demonstrated that the methyl-CpG-binding domain protein 2 (MBD2) mediates vancomycin (VAN)-induced acute kidney injury (AKI). However, the role and regulation of MBD2 in septic AKI are unknown. Herein, MBD2 was induced by lipopolysaccharide (LPS) in Boston University mouse proximal tubules (BUMPTs) and mice. For both in vitro and in vivo experiments, we showed that inhibition of MBD2 by MBD2 small interfering RNA (siRNA) and MBD2-knockout (KO) substantially improved the survival rate and attenuated both LPS and cecal ligation and puncture (CLP)-induced AKI, renal cell apoptosis, and inflammatory factor production. Global genetic expression analyses and in vitro experiments suggest that the expression of protein kinase C eta (PKCη), caused by LPS, is markedly suppressed in MBD2-KO mice and MBD2 siRNA, respectively. Mechanistically, chromatin immunoprecipitation (ChIP) analysis indicates that MBD2 directly binds to promoter region CpG islands of PKCη via suppression of promoter methylation. Furthermore, PKCη siRNA improves the survival rate and attenuates LPS-induced BUMPT cell apoptosis and inflammatory factor production via inactivation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2, which were further verified by PKCη siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKCη/p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKCη/p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI.

Original languageEnglish (US)
Pages (from-to)76-88
Number of pages13
JournalMolecular Therapy - Nucleic Acids
Volume23
DOIs
StatePublished - Mar 5 2021

Keywords

  • AKI
  • ERK1/2
  • MBD2
  • PKCη
  • apoptosis
  • inflammation
  • p38MAPK
  • sepsis

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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