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Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor, and endoplasmic reticulum

Chongshan Dai1, Jichang Li2, Shusheng Tang1

  • 1Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.

Antimicrobial Agents and Chemotherapy
|May 7, 2014
PubMed

Insights

Colistin causes kidney damage through three main apoptosis pathways: mitochondrial, death receptor, and endoplasmic reticulum. Autophagy may protect against this colistin-induced nephrotoxicity.

Area of Science:

  • Nephrology
  • Toxicology
  • Molecular Biology

Background:

  • Colistin nephrotoxicity is a significant clinical challenge, limiting its use.
  • The precise molecular mechanisms underlying colistin-induced kidney damage remain incompletely understood.

Purpose of the Study:

  • To elucidate the roles of mitochondrial, death receptor, and endoplasmic reticulum pathways in colistin nephrotoxicity.
  • To investigate the involvement of apoptosis and autophagy in colistin-induced kidney injury.

Main Methods:

  • Mice received daily intravenous colistin (7.5 or 15 mg/kg) for 7 days.
  • Evaluated renal function, oxidative stress, apoptosis markers, and key proteins in apoptosis and autophagy pathways.
  • Utilized biochemical assays and Western blot analysis.

Main Results:

  • Colistin treatment elevated blood urea nitrogen, serum creatinine, and malondialdehyde, while decreasing superoxide dismutase and catalase activity.
  • Acute tubular necrosis and mitochondrial dysfunction were observed, with evidence of apoptosis via DNA fragmentation, PARP-1 cleavage, 8-OHdG increase, and caspase activation.
  • All three major apoptosis pathways (mitochondrial, death receptor, endoplasmic reticulum) were activated.
  • Autophagy markers (Beclin-1, LC3B) and autophagolysosomes were observed, suggesting a protective role.

Conclusions:

  • Colistin-induced nephrotoxicity involves the activation of mitochondrial, death receptor, and endoplasmic reticulum-mediated apoptosis pathways.
  • Autophagy appears to play a protective role in mitigating colistin-induced kidney damage.
  • This study provides the first comprehensive demonstration of the involvement of these multiple pathways in colistin nephrotoxicity.

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