Cell cycle arrest in a model of colistin nephrotoxicity.
Physiol Genomics
; 45(19): 877-88, 2013 Oct 01.
Article
in En
| MEDLINE
| ID: mdl-23922129
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colistin
/
Cell Cycle Checkpoints
/
Kidney
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Physiol Genomics
Journal subject:
BIOLOGIA MOLECULAR
Year:
2013
Document type:
Article