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A Role for Tubular Necroptosis in Cisplatin-Induced AKI

Yanfang Xu1, Huabin Ma2, Jing Shao2

  • 1Department of Nephrology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China; State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China; Department of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Chinese PLA General Hospital, Beijing, China;

Journal of the American Society of Nephrology : JASN
|March 20, 2015
PubMed

Insights

Necroptosis, a programmed cell death, significantly contributes to cisplatin-induced kidney injury. Inhibiting key necroptosis proteins like RIP1, RIP3, and MLKL protects kidney tubules from damage.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Cell Death Research

Background:

  • Cisplatin-induced acute kidney injury (AKI) involves proximal tubule cell death and inflammation.
  • The precise mechanisms driving these pathological processes remain incompletely understood.

Purpose of the Study:

  • To investigate the role of necroptosis, a form of programmed necrosis, in cisplatin-induced AKI.
  • To elucidate the molecular mechanisms linking cisplatin exposure, necroptosis, and kidney damage.

Main Methods:

  • Utilized gene knockout and chemical inhibitors targeting key necroptosis pathway components (RIP1, RIP3, MLKL) in mouse models and cultured proximal tubular cells.
  • Assessed cisplatin-induced proximal tubule damage and cell death.
  • Investigated the role of inflammatory cytokines (TNF-α, TRAIL, IFN-γ) in necroptosis induction.
  • Examined the impact of RIP1 and RIP3 expression levels on cisplatin-induced necroptosis.

Main Results:

  • Inhibition of RIP1, RIP3, or MLKL significantly reduced cisplatin-induced proximal tubule damage in vivo and in vitro.
  • Cisplatin exposure induced necroptosis in cultured cells, either directly or in combination with upregulated inflammatory cytokines.
  • Increased RIP1 and RIP3 expression enhanced cisplatin-induced necroptosis.
  • RIP3- or MLKL-deficient mice showed diminished inflammatory cytokine upregulation, suggesting a positive feedback loop.

Conclusions:

  • Necroptosis is a critical mechanism underlying proximal tubular cell death in cisplatin-induced nephrotoxic AKI.
  • Targeting the necroptosis pathway presents a potential therapeutic strategy for mitigating cisplatin-induced kidney injury.
Keywords:
cisplatin nephrotoxicitynecroptosisrenal proximal tubule cell

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