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

Abstract

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 ATRinduced 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, H 2 O 2 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.

Molecular Interactions Between Reactive Oxygen Species and Autophagy in Kidney Disease

“…Nrf2 provided a protective role in models of AKI and CKD, including diabetic nephropathy [145,161,162,163,164,165,166]. Lycopene, known to play an antioxidant role, ameliorated atrazine-induced nephrotoxicity by upregulating Nrf2, AMPK, and autophagic flux, as well as by decreasing oxidative stress and p62 levels [167]. Schisandrin B, isolated from the fruit of Schisandra chinensis , provided a protective role in cyclosporine (CsA)-induced nephrotocxicity, attenuated CsA-induced nephrotoxicity by activating Nrf2, preventing ROS accumulation and oxidative stress, and allowed recovery of CsA-induced blockade of autophagic flux [168].…”

Nephroprotective activity of natural products against chemical toxicants: The role of Nrf2/ARE signaling pathway

“…By promoting HO‐1 and NQO‐1 genes downstream, Nrf2 increased the level of phase‐II enzymes such as SOD, CAT, and GSH‐Px and lowered the autophagy‐related genes (Beclin‐1 and ATGs) and proteins (p62/SQSTM and LC3). This beneficial property of lycopene has been shown to reduce renal toxicity caused by atrazine (Lin, Bayarsengee, et al., 2018; Lin, Xia, et al., 2018).…”

New Insights into the Nrf-2/HO-1 Signaling Axis and Its Application in Pediatric Respiratory Diseases

“…When stimulated by external injury, proper induction of autophagy can reduce injury to the body [26]. Lin et al discovered a crosstalk between AMPK-activated autophagy and the Nrf2 signaling axis in lycopene- (LYC-) mediated nephroprotection against atrazine- (ATR-) induced toxicity in mouse kidneys [27]. Yao found that the activation of the Nrf2/HO-1 signaling axis can prevent vascular calcification induced by hyperphosphatemia by inducing autophagy in renal vascular smooth muscle cells [28].…”