Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway.
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.
College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
Chongshan
C
Dai
College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
Shusheng
S
Tang
College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
Sijun
S
Deng
College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
Shen
S
Zhang
College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
Yan
Y
Zhou
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
Tony
T
Velkov
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia xiaoxl@cau.edu.cn colistin.polymyxin@gmail.com.
Jian
J
Li
College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China xiaoxl@cau.edu.cn colistin.polymyxin@gmail.com.
Xilong
X
Xiao
D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects; D001806:Blood Urea Nitrogen; D002338:Carotenoids / Q000494:pharmacology*; D003091:Colistin / Q000009:adverse effects*; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D000077276:Lycopene; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008815:Mice, Inbred Strains; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D020011:Protective Agents; D002338:Carotenoids; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000077276:Lycopene; D003091:Colistin