TY - JOUR T1 - Human Pluripotent Stem Cell Derived Kidney Model for Nephrotoxicity Studies JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.082727 SP - dmd.118.082727 AU - Piyush Bajaj AU - A. David Rodrigues AU - Claire M Steppan AU - Sandra J Engle AU - Sumathy Mathialagan AU - Thomas Schroeter Y1 - 2018/01/01 UR - http://dmd.aspetjournals.org/content/early/2018/08/31/dmd.118.082727.abstract N2 - Current in vitro models for identifying nephrotoxins are poorly predictive. Human pluripotent stem cells (hPSCs) were differentiated into three dimensional, multicellular structures containing proximal tubule cells (PTCs) and podocytes and evaluated as a platform for predicting nephrotoxicity. PTCs showed megalin-dependent, cubilin-mediated endocytosis of fluorescently labeled dextran and active gamma-glutamyl transpeptidase enzymes. Transporters from both the ABC and the SLC families were present at physiological levels in the differentiated cells, however, important renal transporters such as OAT1, OAT3, and OCT2 were present only at lower levels. Radioactive uptake studies confirmed the functional activity of OCTN2, OAPT4C1, and OCTs/MATEs. When treated with ten pharmacological agents as a test of the platform, known nephrotoxic compounds were distinguished from more benign compounds by an increase in tubular (PTC, KIM-1 and HO-1) and glomerular (NPHS1/WT1) markers associated with nephrotoxicity and we were able to distinguish the type of nephrotoxin by examining the relative levels of these markers. Given the functions demonstrated and with improved expression of key renal transporters, this hPSC-derived in vitro kidney model shows promise as a platform for detection of mechanistically different nephrotoxins. ER -