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METTL3-mediated M6A methylation modification is involved in colistin-induced nephrotoxicity through apoptosis

Chunli Xia1, Jian Wang1, Zhiyong Wu1

  • 1College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.

Toxicology
|September 24, 2021
PubMed

Insights

Colistin antibiotic use causes kidney cell death by disrupting RNA methylation. This study reveals N-methyladenosine (m6A) RNA methylation is crucial in preventing colistin-induced nephrotoxicity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Toxicology

Background:

  • Colistin is a vital last-line antibiotic for multi-drug resistant Gram-negative infections.
  • Colistin's nephrotoxicity is a significant clinical concern, necessitating a deeper understanding of its mechanisms.
  • N-methyladenosine (m6A) RNA methylation plays a critical role in RNA metabolism and kidney development.

Purpose of the Study:

  • To investigate the role of m6A RNA methylation in colistin-induced nephrotoxicity.
  • To elucidate the molecular mechanisms underlying colistin's damaging effects on kidney cells.
  • To explore the relationship between RNA decay, apoptosis, and oxidative stress in colistin nephrotoxicity.

Main Methods:

  • Induction of nephrotoxicity in mouse models using colistin.
  • Assessment of kidney apoptosis using histological and molecular indicators.
  • Quantification of m6A RNA methylation levels and METTL3 expression.
  • Analysis of oxidative stress markers and ATPase activities.

Main Results:

  • Colistin treatment induced significant kidney apoptosis, characterized by morphological changes and altered apoptosis-related gene expression.
  • A notable decrease in m6A RNA methylation levels was observed in colistin-treated kidneys.
  • Downregulation of METTL3 mRNA and protein correlated with increased apoptosis, suggesting its protective role.
  • Colistin exposure led to increased oxidative stress and altered ATPase activities.

Conclusions:

  • m6A RNA methylation is implicated in the mechanism of colistin nephrotoxicity.
  • The findings suggest that colistin-induced nephrotoxicity involves oxidative stress-mediated apoptosis.
  • METTL3 and m6A methylation may represent potential targets for mitigating colistin-induced kidney damage.
Keywords:
ApoptosisColistinNephrotoxicityOxidative stressm6A methylation modification

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