LAUSR

Uranium (U) induces generation of excessive intracellular reactive oxygen species (ROS), which is generally considered as a possible mediator of U‐triggered kidney tubular cells injury and nephrotoxicity. Our goal is designed to elucidate that the precise molecular mechanism in ROS downstream is association with U‐induced NRK‐52E cells apoptosis. The results show that U intoxication in NRK‐52E cells reduced cell activity and triggered apoptosis, as demonstrated by flow cytometry and apoptotic marker cleaved Caspase‐3 expression. U exposure triggered endoplasmic reticulum (ER) stress, which is involvement of apoptosis determined by marker molecules including GRP78, PERK, IRE1, ATF6, CHOP, cleaved Caspase‐12, and Caspase‐3. Administration of antioxidant N‐acetylcysteine (NAC) effectively blocked U‐triggered ROS generation, ER stress, and apoptosis. U contamination evidently decreased the expression of phosphorylation PI3K, AKT, and mTOR and ratios of their respective phosphorylation to the corresponding total proteins. Application of a PI3K activator IGF‐1 significantly abolished these adverse effects of U intoxication on PI3K/AKT/mTOR signaling and subsequently abrogated U‐triggered apoptosis. NAC also effectively reversed down‐regulation of phosphorylated PI3K induced by U exposure. Taken together, these data strongly suggest that U treatment induces NRK‐52E cells apoptosis through ROS production, ER stress, and down‐regulation of PI3K/AKT/mTOR signaling. Targeting ROS formation‐, ER stress‐, and PI3K/AKT/mTOR pathway‐mediated apoptosis could be a novel approach for attenuating U‐triggered nephrotoxicity.