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

Yuxin Xie1,2, Bohao Liu1,2, Jian Pan1,2

  • 1Department of Emergency Medicine, Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.

Molecular Therapy. Nucleic Acids
|December 18, 2020
PubMed

Insights

Methyl-CpG-binding domain protein 2 (MBD2) drives septic acute kidney injury (AKI) by activating protein kinase C eta (PKCη) and downstream signaling pathways. Inhibiting MBD2 shows promise for treating septic AKI.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Immunology

Background:

  • Methyl-CpG-binding domain protein 2 (MBD2) is implicated in vancomycin-induced acute kidney injury (AKI).
  • The role of MBD2 in septic AKI remains unclear.
  • Septic AKI is a critical condition with high mortality.

Purpose of the Study:

  • To investigate the role and regulation of MBD2 in septic AKI.
  • To elucidate the molecular mechanisms by which MBD2 contributes to septic AKI.
  • To evaluate MBD2 as a potential therapeutic target for septic AKI.

Main Methods:

  • In vitro studies using Boston University mouse proximal tubules (BUMPTs) and in vivo experiments in mice.
  • Utilized MBD2 small interfering RNA (siRNA) and MBD2-knockout (KO) models.
  • Assessed survival rates, AKI markers, apoptosis, inflammatory factors, gene expression, chromatin immunoprecipitation (ChIP), and Western blotting.

Main Results:

  • MBD2 inhibition (siRNA and KO) significantly improved survival and attenuated LPS and cecal ligation and puncture (CLP)-induced AKI, apoptosis, and inflammation.
  • MBD2 deficiency suppressed lipopolysaccharide (LPS)-induced protein kinase C eta (PKCη) expression.
  • MBD2 directly binds to the PKCη promoter, regulating its methylation and expression.
  • PKCη inactivation ameliorated LPS-induced BUMPT cell apoptosis and inflammation via the p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2 pathways.
  • MBD2-KO mice showed reduced septic AKI via inactivation of the PKCη/p38MAPK/ERK1/2 axis.

Conclusions:

  • MBD2 mediates septic AKI by activating the PKCη/p38MAPK/ERK1/2 signaling pathway.
  • MBD2 inhibition represents a potential therapeutic strategy for septic AKI.
  • Understanding MBD2's regulatory role in septic AKI provides new insights into kidney injury mechanisms.
Keywords:
AKIERK1/2MBD2PKCηapoptosisinflammationp38MAPKsepsis

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