GSE195642
Human iPSC-derived renal organoids engineered to report oxidative stress can predict drug-induced nephrotoxicity
The purpose of this study was primarily to find a reporter of nephrotoxicity that could be engineered into human pluripotent stem cells, and then to assess the performance of that reporter using a panel of test compounds. We treated renal organoids with two different concentrations of Gentamicin, 1mg/ml (low concentration) and 4 mg/ml (high concentration), and used RNA-seq to compare the expression profile of these groups to the expression profile of untreated control group. In our RNA-seq analyses, the profile of the 4 mg/ml gentamicin-treated samples was strikingly different from that of the control group.There were no genes expressed significantly differently between the control and the 1 mg/ml gentamicin-treated samples. classical markers of nephrotoxicity were either not up-regulated in response to injury (CLU) or were down-regulated (NGAL) in response to the known nephrotoxicant gentamicin. Among the transcripts showing increased expression was KIM-1 (log fold-change: 1.67; FDR-corrected p = 0.03), a biomarker commonly associated with renal tubular necrosis. Expression of the oxidative stress marker HMOX1 was also highly increased (log fold-change: 6.55; FDR-corrected p = 0.00015).  Based on the intersection of HMOX1 in several different toxicity pathways as well as its greater level of up-regulation, we identified HMOX1 as a potentially promising reporter for one large class of nephrotoxicants; those in which the OS pathway is activated. Overall design: Nine samples were included and are divided into three groups;control (untreated) group, low-dose-gentamicin-treated group, and high-dose-gentamicin-treated group. Each group includes three different repeats