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Trimethylamine N-oxide Induced Chronic Kidney Injury by Triggering PANoptosis

D Shao1, L Bai, Q Chen

  • 1Department of Clinical Diagnostics, Hebei Medical University, Hebei, China. wuym@hebmu.edu.cn.

Physiological Research
|August 31, 2025
PubMed

Insights

Trimethylamine N-oxide (TMAO) contributes to kidney disease by inducing PANoptosis, a form of regulated cell death involving pyroptosis, apoptosis, and necroptosis, leading to kidney fibrosis and impaired function.

Area of Science:

  • Biochemistry
  • Nephrology
  • Cellular Biology

Background:

  • Trimethylamine N-oxide (TMAO) is linked to kidney disease progression.
  • The precise mechanisms of TMAO-induced kidney injury remain largely unknown.
  • Regulated cell death pathways are implicated in various organ injuries.

Purpose of the Study:

  • To investigate the role of regulated cell death in trimethylamine N-oxide (TMAO)-induced chronic kidney injury.
  • To elucidate the specific cell death pathways activated by TMAO in the kidneys.

Main Methods:

  • A mouse model of chronic kidney injury was established via daily intraperitoneal injection of TMAO for three months.
  • Kidney function was assessed by measuring plasma creatinine and blood urea nitrogen levels.
  • Kidney pathology, fibrosis, and the expression of key proteins involved in apoptosis, necroptosis, pyroptosis, and iron metabolism were analyzed using Masson staining and Western blotting.

Main Results:

  • TMAO administration significantly elevated plasma creatinine and blood urea nitrogen levels, indicating impaired kidney function.
  • Histological analysis revealed increased kidney fibrosis in the TMAO-treated group.
  • Western blot analysis demonstrated significantly upregulated expression of proteins associated with PANoptosis (caspase-8, NLRP3, IL-1beta, GSDMD, ZBP1, RIP3, MLKL) and iron homeostasis (TFR1, FTH, FPN, NRF2, GPX4), without changes in iron or MDA levels.

Conclusions:

  • PANoptosis, encompassing pyroptosis, apoptosis, and necroptosis, is a key mechanism contributing to TMAO-induced chronic kidney injury.
  • TMAO-induced kidney damage involves complex cellular death pathways and alterations in iron metabolism regulators.
  • These findings provide novel insights into the pathogenesis of TMAO-related nephropathy and suggest potential therapeutic targets.

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