Fig. 8. Proposed mechanism of kidney cell cytotoxicity induced by uranium(vi) (uranyl acetate). When uranium enters into the kidney cells, excessive intracellular reactive oxygen species (ROS) are generated either by uranium radioactivity or chemical properties or both,34 which can alter the cellular redox state. This increases MDA content, depletes GSH levels, and impairs SOD and CAT activities. Excessive intracellular ROS decrease Nrf2 protein expression, nuclear translocation and accumulation. Reduced nuclear Nrf2 levels could mediate in the down-regulation of CBS and CSE gene expression, resulting in a reduction of endogenous H2S formation, which could be involved in uranium-induced kidney cell cytotoxicity. Likewise, excessive intracellular ROS directly decrease the level of ROS-scavenging endogenous H2S. Dotted lines represent endogenous signaling pathways that participate in the regulation of the GSK-3/β-TrCP axis.15,16 Whether these signaling pathways could be activated by uranium intoxication needs to be explored further.
