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The MAD2B-APC/C-MDM2 axis mediates acute kidney injury by modulating p53

Zhe Hao1, Qian Yuan1, Hui Tang1

  • 1Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The FEBS Journal
|April 1, 2023
PubMed

Insights

Mitotic arrest deficient 2 like 2 (MAD2B) suppresses p53 in acute kidney injury (AKI). Loss of MAD2B worsens AKI by increasing p53, but targeting MAD2B may offer therapeutic benefits.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Biology

Background:

  • p53 is a key regulator in acute kidney injury (AKI) progression.
  • The precise mechanisms controlling p53 in AKI require further elucidation.
  • The role of Mitotic arrest deficient 2 like 2 (MAD2B) in AKI is currently unknown.

Purpose of the Study:

  • To investigate the role of MAD2B in the context of AKI.
  • To elucidate the regulatory relationship between MAD2B and p53 in kidney injury.
  • To explore MAD2B as a potential therapeutic target for AKI.

Main Methods:

  • Utilized a conditional knockout mouse model for MAD2B.
  • Induced AKI using cisplatin in experimental models.
  • Investigated the activation of the anaphase-promoting complex/cyclosome (APC/C) and MDM2.
  • Administered the APC/C antagonist proTAME to assess therapeutic effects.

Main Results:

  • MAD2B deficiency exacerbated cisplatin-induced AKI, characterized by increased p53, renal dysfunction, G1 arrest, and apoptosis.
  • MAD2B deficiency led to APC/C activation, reduced MDM2 levels, and subsequent p53 accumulation.
  • Treatment with proTAME ameliorated AKI, reduced p53 upregulation, and mitigated tubular cell G1 arrest and apoptosis.

Conclusions:

  • MAD2B functions as an endogenous suppressor of p53 in AKI.
  • MAD2B deficiency promotes AKI progression through p53 upregulation via APC/C and MDM2 pathways.
  • Targeting MAD2B presents a novel strategy for ameliorating AKI.
Keywords:
AKIMAD2Bapoptosiscell cycle arrestp53

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