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.