Cell cycle arrest in a model of colistin nephrotoxicity

Michael Eadon, Bradley K. Hack, Jessy J. Alexander, Chang Xu, M. Eileen Dolan, Patrick N. Cunningham

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Colistin (polymixin E) is an antibiotic prescribed with resurging frequency for multidrug resistant gram negative bacterial infections. It is associated with nephrotoxicity in humans in up to 55% of cases. Little is known regarding genes involved in colistin nephrotoxicity. A murine model of colistin-mediated kidney injury was developed. C57/BL6 mice were administered saline or colistin at a dose of 16 mg/kg/day in 2 divided intraperitoneal doses and killed after either 3 or 15 days of colistin. After 15 days, mice exposed to colistin had elevated blood urea nitrogen (BUN), creatinine, and pathologic evidence of acute tubular necrosis and apoptosis. After 3 days, mice had neither BUN elevation nor substantial pathologic injury; however, urinary neutrophil gelatinase-associated lipocalin was elevated (P = 0.017). An Illumina gene expression array was performed on kidney RNA harvested 72 h after first colistin dose to identify differentially expressed genes early in drug treatment. Array data revealed 21 differentially expressed genes (false discovery rate < 0.1) between control and colistin-exposed mice, including LGALS3 and CCNB1. The gene signature was significantly enriched for genes involved in cell cycle proliferation. RT-PCR, immunoblot, and immunostaining validated the relevance of key genes and proteins. This murine model offers insights into the potential mechanism of colistin-mediated nephrotoxicity. Further studies will determine whether the identified genes play a causative or protective role in colistin-induced nephrotoxicity.

Original languageEnglish (US)
Pages (from-to)877-888
Number of pages12
JournalPhysiological Genomics
Volume45
Issue number19
DOIs
StatePublished - Oct 1 2013

Fingerprint

Colistin
Cell Cycle Checkpoints
Genes
Blood Urea Nitrogen
Gram-Negative Bacterial Infections
Galectin 3
Kidney
Wounds and Injuries
Genetic Association Studies
Creatinine
Cell Cycle
Necrosis
Cell Proliferation
RNA
Apoptosis
Anti-Bacterial Agents

Keywords

  • Cell cycle
  • Colistin
  • Galectin-3
  • Nephrotoxicity
  • Polymyxin E
  • Renal failure

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Eadon, M., Hack, B. K., Alexander, J. J., Xu, C., Dolan, M. E., & Cunningham, P. N. (2013). Cell cycle arrest in a model of colistin nephrotoxicity. Physiological Genomics, 45(19), 877-888. https://doi.org/10.1152/physiolgenomics.00076.2013

Cell cycle arrest in a model of colistin nephrotoxicity. / Eadon, Michael; Hack, Bradley K.; Alexander, Jessy J.; Xu, Chang; Dolan, M. Eileen; Cunningham, Patrick N.

In: Physiological Genomics, Vol. 45, No. 19, 01.10.2013, p. 877-888.

Research output: Contribution to journalArticle

Eadon, M, Hack, BK, Alexander, JJ, Xu, C, Dolan, ME & Cunningham, PN 2013, 'Cell cycle arrest in a model of colistin nephrotoxicity', Physiological Genomics, vol. 45, no. 19, pp. 877-888. https://doi.org/10.1152/physiolgenomics.00076.2013
Eadon, Michael ; Hack, Bradley K. ; Alexander, Jessy J. ; Xu, Chang ; Dolan, M. Eileen ; Cunningham, Patrick N. / Cell cycle arrest in a model of colistin nephrotoxicity. In: Physiological Genomics. 2013 ; Vol. 45, No. 19. pp. 877-888.
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