Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Abstract

bNephrotoxicity 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-B 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.

Colistin-Induced Apoptosis of Neuroblastoma-2a Cells Involves the Generation of Reactive Oxygen Species, Mitochondrial Dysfunction, and Autophagy

“…This indicates colistin treatment decreases the neurons capacity to breakdown superoxide anions and hydroxyl radicals; further exacerbating ROS mediated oxidative stress. Coincidently, we have previously demonstrated that the co-administration of antioxidants such as lycopene have been shown to be protective against polymyxin-induced nephrotoxicity in mice[35]. This supports the notion that oxidative stress pathways play an important role in polymyxin-induced neuro-cytotoxicity.…”

Cellular Uptake and Localization of Polymyxins in Renal Tubular Cells Using Rationally Designed Fluorescent Probes

“…Mitochondria and ER form structural and functional networks essential for maintenance of cellular homeostasis and determine the cell fate under various pathophysiological conditions, including oxidative stress (31). This correlates with the current literature evidence that both the ER and mitochondrial pathways are involved in polymyxin-induced nephrotoxicity (16,30,32). Recently, it was reported that activation of the death receptor and mitochondrial pathways is involved in polymyxin-induced apoptosis in NRK-52E cells (15,30).…”

Colistin-induced nephrotoxicity and the role of N-acetylcysteine: a retrospective cohort study

“…Nephrotoxicity is usually reversible but can sometimes result in chronic kidney disease (CKD) [6]. Oxidative stress plays an important role in the pathogenesis of COL-induced nephrotoxicity so the protective effects of antioxidative agents, such as ascorbic acid, lycopene, and N-acetylcysteine [NAC] have been investigated recently [2,7,8]. NAC is commonly used as a mucolytic agent, but it has powerful anti-inflammatory and antioxidant activities [9].…”