Cell cycle arrest in a model of colistin nephrotoxicity.
Physiol Genomics, 2013/10/01;45(19):877-88.
Eadon MT[1], Hack BK, Alexander JJ, Xu C, Dolan ME, Cunningham PN
Affiliations
PMID: 23922129DOI: 10.1152/physiolgenomics.00076.2013
Impact factor: 4.297
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.
Keywords: cell cycle; colistin; galectin-3; nephrotoxicity; polymyxin E; renal failure
MeSH terms
Animals; Body Weight; Cell Cycle Checkpoints; Cluster Analysis; Colistin; Disease Models, Animal; Galectin 3; Gene Expression Profiling; In Situ Nick-End Labeling; Kidney; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Necrosis; Proliferating Cell Nuclear Antigen; Reproducibility of Results
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