Cell cycle arrest in a model of colistin nephrotoxicity.
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.
Divisions of Nephrology and Clinical Pharmacology, Indiana University, Indianapolis, Indiana;
Michael T
MT
Eadon
Bradley K
BK
Hack
Jessy J
JJ
Alexander
Chang
C
Xu
M Eileen
ME
Dolan
Patrick N
PN
Cunningham
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D016000:Cluster Analysis; D003091:Colistin / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D037502:Galectin 3 / Q000378:metabolism; D020869:Gene Expression Profiling; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D015203:Reproducibility of Results
D037502:Galectin 3; D018809:Proliferating Cell Nuclear Antigen; D003091:Colistin
cell cycle; colistin; galectin-3; nephrotoxicity; polymyxin E; renal failure