Precise Monitoring of Drug-Induced Kidney Injury Using an Endoplasmic Reticulum-Targetable Ratiometric Time-Gated Luminescence Probe for Superoxide Anions.

Abstract

Drug-induced acute kidney injury (AKI), caused by renal drug metabolism, has been considered a major barrier in drug development and clinical treatment. Among various drugs, anti-cancer drug cisplatin and aminoglycoside antibiotic gentamicin, are known to be able to induce excessive or unfolded accumulation of proteins in endoplasmic reticulum (ER) of cells, leading to ER stress. Meanwhile reactive oxygen species (ROS) are formed, and superoxide anion (O2•-), the first produced ROS, is a key species to induce the AKI. Due to the lack of appropriate tools, the early diagnosis of AKI induced by cisplatin, gentamicin or other drugs is still a crucial challenge. Herein we report a lanthanide complex-based ER-targetable luminescence probe for O2•-, ER-NFTTA-Eu3+/Tb3+, for the sensitive monitoring of drug-induced AKI via mapping the generation of O2•- in live cells and laboratory animals. Using this probe coupled with ratiometric time-gated luminescence (RTGL) imaging technique, the changes of O2•- level in ER of live cells induced by different stimuli were precisely monitored. More importantly, the substantial increases in O2•- levels were observed in the cisplatin- and gentamicin-induced kidney injury of mice. In addition, the protective effects of L-carnitine (LC) and epigallocatechin-3-gallate (EGCG) against cisplatin- and gentamicin-induced nephrotoxicity were visualized and elucidated for the first time. The results demonstrated the potential of ER-NFTTA-Eu3+/Tb3+ for examining and monitoring O2•- in drug-induced AKI, and for serving to the diagnosis and treatment of nephrotoxicity diseases.