Lycopene Triggers Nrf2–AMPK Cross Talk to Alleviate Atrazine-Induced Nephrotoxicity in Mice

• Published in: Journal of agricultural and food chemistry 2018-11, Vol.66 (46), p.12385-12394
• Main Authors: Lin, Jia, Xia, Jun, Zhao, Hua-Shan, Hou, Rui, Talukder, Milton, Yu, Lei, Guo, Jian-Ying, Li, Jin-Long
• Format: Article
• Language: English
• Subjects: Animals; Atrazine - toxicity; Autophagy - drug effects; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Herbicides - toxicity; Humans; Hydrogen Peroxide - metabolism; Kidney - drug effects; Kidney - metabolism; Kidney Diseases - drug therapy; Kidney Diseases - etiology; Kidney Diseases - genetics; Kidney Diseases - metabolism; Lycopene - administration & dosage; Male; Mice; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Oxidative Stress - drug effects; Protein Kinases - genetics; Protein Kinases - metabolism; Son of Sevenless Protein, Drosophila - genetics; Son of Sevenless Protein, Drosophila - metabolism
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/acs.jafc.8b04341

Atrazine (ATR), an environmental persistent and bioaccumulative herbicide, has been associated with environmental nephrosis. Lycopene (LYC) exhibits important properties of nephroprotection, but there are limited data on the specific underlying mechanism. The primary objective of this study was to explore the therapeutic effect of LYC on ATR-induced nephrotoxicity in mice. The mice were divided randomly into 6 groups and treated as follows: control group (C), 5 mg/kg LYC group (L), 50 mg/kg ATR group (A1), 200 mg/kg ATR group (A2), 50 mg/kg ATR plus 5 mg/kg LYC group (A1+L), and 200 mg/kg ATR plus 5 mg/kg LYC group (A2+L) by oral gavage administration for 21 days. We found that pretreatment with LYC significantly suppressed the ATR-induced renal tubular epithelial cell swelling. Furthermore, LYC mitigated ATR-induced dysregulation of oxidative stress markers by reducing MDA, H2O2 levels, and increasing SOD, GPx, CAT concentration, and Nrf2 activation. Moreover, LYC activated the autophagic flux by a detectable change in autophagy-related genes (Beclin-1 and ATGs) and proteins (p62/SQSTM) and by the formation of autophagic vacuole (AV) and LC3 aggregation, in parallel with AMPK activation (pAMPK/AMPK). Herein, ATR-up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and Nrf2-regulated redox genes, including quinoneoxidoreductase-1 (NQO1) and heme oxidase-1 (HO1), whereas LYC down-regulated those of the above genes. In addition, LYC suppressed ATR-induced activation of autophagy (increased LC3II/LC3I, ATGs, Beclin1, and p62, in parallel with increased AMPK activation). Collectively, our findings identified a cross talk between AMPK-activated autophagy and the Nrf2 signaling pathway in LYC-mediated nephroprotection against ATR-induced toxicity in mice kidney.