Identification of in vitro nephrotoxic biomarkers

Identification of in vitro nephrotoxic biomarkers based on co-culture platforms of hepatocytes and kidney cells


Eun-Hee Lee, Se-Myo Park, Heeyoung Yang, Mi-Sook Dong, Mi-Sun Choi, Soojin Kim, Jaehwan Ahn, Seokjoo Yoon and Jung-Hwa Oh


Eun-Hee Lee


Korea Institute of Toxicology


Recently, various in vitro systems have been developed to predict drug-induced nephrotoxicity quickly and simply. However, the biggest problem for the nephrotoxicity screening technologies is that biological conditions such as drug metabolism of in vivo systems are not immediately reflected in in vitro systems. In order to screen nephrotoxicity by reflecting metabolic conditions, a co-culture platform was developed with hepatocyte cell lines (HepG2), endothelial cell lines (HUVEC) and kidney cell lines (HK-2). In particular, to overcome the problem of low expression of cytochromes P450 (CYPs), HepG2 cell line was developed to stably overexpress the CYPs. In this study, 10 representative renal toxicants were treated in a co-culture system and gene expression profiling was analyzed respectively from HK-2 cells. Gene expression profiling showed that the toxicological functions involved in inflammation, necrosis and cell death, and the representative canonical pathways were identified according to the tested drugs. Certain common genes were selected from 10 reference nephrotoxic drugs based on co-culture system and these genes may potentially be used as predictive in vitro biomarkers for screening drug-induced nephrotoxicity. This work was supported by a grant (13182MFDS988, NRF-2016M3A9C4953144) from the Ministry of Food and Drug Safety and the Ministry of Science, ICT, and Future Planning.