Directly reprogrammed renal tubular epithelial cells are sensitive to typical metabolic alterations occurring in hyperglycemia

Forced expression of four transcription factors are sufficient to reprogram mouse embryonic fibroblasts (MEFs) directly to induced renal tubular epithelial cells (iRECs). These cells have been characterized as tubule cells by transcriptomic, morphological and functional studies. Recently, we analyzed iRECs by untargeted metabolomics and thereby proved their cellular identity. Hence, changes by application of a common nephrotoxic agent confirmed many alterations occurring in vivo [in submission]. In this study, we investigated the impact of glucose on MEFs and iRECs by conducting an untargeted gas chromatography/mass spectrometry based profiling with high and low glucose concentrations. Whereas accumulating in MEFs used for reprogramming, glucose was efficiently metabolized by glycolysis and citric acid cycle in iRECs but also an increase in the polyol pathway was observed. The activation of this pathway and a consequent generation of reactive oxygen species is a common phenomenon in diabetic complications such as diabetic retinopathy, neuropathy and nephropathy (DN). Thus, iRECs transpired to be an excellent in vitro model for tubule damage, an aspect of DN being overshadowed by the glomerular focus. The possibility to generate iRECs also from human fibroblasts holds great potential in patient specific testing for exogenous challenges in general.