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CUL4B protects kidneys from acute injury by restraining p53/PAI-1 signaling

Kaixuan Liu1, Xiaoyu Hao1, Yangfan Gao2

  • 1Key Laboratory of Experimental Teratology, Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.

Cell Death & Disease
|December 18, 2024
PubMed

Insights

Cullin 4B (CUL4B) protects kidneys from acute injury by suppressing PAI-1 expression. Loss of CUL4B worsens kidney damage, inflammation, and cell death, highlighting its protective role in acute kidney injury.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cellular Biology

Background:

  • Acute kidney injury (AKI) presents significant morbidity and mortality.
  • Understanding novel mechanisms is crucial for developing therapeutic strategies.
  • Cullin 4B (CUL4B) is a key component of the CRL4B E3 ubiquitin ligase complex.

Purpose of the Study:

  • To investigate the role of CUL4B in kidney protection against acute injury.
  • To elucidate the molecular mechanisms by which CUL4B exerts its protective effects.

Main Methods:

  • Utilized mouse models of cisplatin-induced and ischemia-reperfusion (IR) kidney injury.
  • Assessed renal injury, inflammation, and apoptosis in wild-type and Cul4b-deficient kidneys.
  • Performed transcriptome analysis to identify affected pathways.
  • Investigated the interaction between CUL4B, p53, and PAI-1.

Main Results:

  • CUL4B expression is upregulated in tubular epithelial cells (TECs) following cisplatin or IR injury.
  • Loss of CUL4B exacerbates renal injury, inflammation, and TEC apoptosis.
  • Cul4b deficiency leads to increased PAI-1 expression.
  • CUL4B suppresses PAI-1 by promoting p53 polyubiquitination and degradation.
  • Inhibiting PAI-1 or p53 ameliorates the exacerbated injury in Cul4b-deficient kidneys.

Conclusions:

  • CUL4B plays a significant kidney-protective role against acute injury.
  • CUL4B mitigates AKI by suppressing PAI-1 expression via p53 degradation.
  • Targeting the CUL4B-p53-PAI-1 axis may offer a therapeutic avenue for AKI.

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