Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway

Abstract

Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

FIG 1

Structure of lycopene.

FIG 2

Representative histopathological results and the semiquantitative scores. (A) Control group: no marked injury. (B) Lycopene group: no marked injury. (C) Colistin (15 mg/kg/day) group: marked tubular damage with necrosis and exfoliation of epithelial cells (arrows), cast formation (arrowheads), and dilation. (D) Colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) (Colistin/lycopene 5) group: mild tubular damage with necrosis (arrows) of epithelial cells and cast formations (arrowheads). (E) Colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) (Colistin/lycopene 20) group: minor tubular damage with tubular dilatation (arrows) and cast formations (arrowheads). (F) SQS values are presented as means ± SD (n = 4). **, P < 0.01 (compared to the control group); #, P < 0.05; ##, P < 0.01 (compared to the colistin group). Data represent the results of H&E staining. Bars, 100 μm.

FIG 3

Activities of caspase-3 (A), caspase-9 (B), and HO-1 (C). Values are presented as means ± SD (n = 10). **, P < 0.01 (compared to the control group); #, P < 0.05; ##, P < 0.01 (compared to the colistin group).

FIG 4

Expression of Nrf2 (A), OH-1 (B), and NF-κB (C) in the kidney. Values are presented as means ± SD (n = 10). *, P < 0.05; **, P < 0.01 (compared to the control group); #, P < 0.05; ##, P < 0.01 (compared to the colistin group).