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Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway
Chongshan Dai1, Shusheng Tang1, Sijun Deng1
1College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
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.
Insights
Lycopene protects against colistin-induced nephrotoxicity in mice by reducing kidney damage and oxidative stress. This antioxidant effect is linked to activating the Nrf2/HO-1 pathway, offering a potential therapeutic strategy.
Area of Science:
- Pharmacology and Toxicology
- Nephrology
- Antioxidant Research
Background:
- Colistin is crucial for treating multidrug-resistant Gram-negative bacterial infections.
- Nephrotoxicity is a significant dose-limiting side effect of colistin therapy.
- Novel strategies are needed to mitigate colistin-induced kidney damage.
Purpose of the Study:
- To evaluate the protective effects of lycopene against colistin-induced nephrotoxicity in a mouse model.
- To investigate the underlying mechanisms, including oxidative stress and apoptosis pathways.
Main Methods:
- A mouse model was used with five groups: control, lycopene alone, colistin alone, and colistin combined with two different lycopene doses.
- Kidney function was assessed via blood urea nitrogen (BUN) and serum creatinine levels.
- Kidney tissues were analyzed for oxidative stress biomarkers, apoptosis, histopathology, and gene expression (NF-κB, Nrf2, HO-1) via qRT-PCR.
Main Results:
- Colistin significantly elevated BUN and creatinine, increased tubular apoptosis/necrosis, lipid peroxidation, and HO-1 activity, while decreasing GSH, CAT, and SOD levels.
- Lycopene treatment (5 and 20 mg/kg) attenuated these colistin-induced changes.
- Lycopene (20 mg/kg) significantly downregulated NF-κB and upregulated Nrf2 and HO-1 mRNA expression in kidney tissues.
Conclusions:
- Lycopene, particularly at 20 mg/kg/day, effectively protects against colistin-induced nephrotoxicity in mice.
- The protective mechanism involves lycopene's antioxidant properties and activation of the Nrf2/HO-1 signaling pathway.
