DEVELOPMENT OF HUMAN IN VITRO MODELS FOR PREDICTING ORGAN-SPECIFIC TOXICITY

Abstract

The human kidney is a major target organ for drug-induced toxicity. There is currently a lack of reliable pre-clinical models for predicting nephrotoxicity due to the lack of appropriate cell types and endpoints. The goal of my thesis was to develop an in vitro model that predicts nephrotoxicity in humans with high accuracy. My work focused on the use of renal proximal tubular cells (PTCs), and increases in mRNA expression levels of interleukin (IL)-6 and IL-8 were identified as potential endpoints. This in vitro model was validated with 41 well-characterized compounds and the results indicated that 76% - 85% of predictions made with this model would be correct. Similar results were also obtained with stem cell-derived renal-like cells, demonstrating their first successful application. Further, the underlying mechanisms of interleukin up-regulation in PTCs were investigated, providing further insights into the role of pro-inflammatory pathways in drug-induced nephrotoxicity.