S4: Developing quantitative AOPs
Developing quantitative AOPs of renal toxicity with Effectopedia
Medical University of Innsbruck, Division of Physiology
Alice Limonciel, Anja Wilmes, Giada Carta and Paul Jennings
Within the kidney, the proximal tubule (PT) is particularly sensitive to xenobiotics due primarily to its multiple uptake routes that include megalin/cubilin, organic anion transporters, peptide transporters and organic cation transporters. Sustaining these transporting activities is a high mitochondrial content that makes PT cells particularly susceptible to mitochondrial injury and oxidative stress in general. The PT has a limited rejuvenation potential so any compound injuring this area has a high risk of initiating or accelerating chronic kidney disease (CKD). Molecular toxicology, coupled with in vitro techniques, has in recent years greatly increased our knowledge of chemical-induced cellular perturbations, which can facilitate the prediction of what is likely to occur in an entire organism. However, in order for such information to be useful for regulatory acceptance it must be structured in a formal way. The OECD is promoting the construction of Adverse Outcome Pathways (AOPs) to link chemical-induced cellular perturbations to disease states. An AOP begins with a molecular initiating event (MIE), early key events (KEs) and cascading KEs leading to the adverse outcome. Our renal AOPs begin with chemical uptake from the lumen and/or interstitium, with a first focus on oxidative stress as a highly relevant MIE in the PT. Early KEs encompass mitochondrial injury, ER stress and DNA damage, activating stress response pathways such as Nrf2, HIF-1 alpha, unfolded protein response and p53. Loss of PT transport function, including tight junction remodeling and decreased mitochondrial respiration are later KEs, which lead to a Fanconi-like phenotype. Finally, KEs such as cellular senescence or cell death will lead to nephron attrition, decreased renal function and CKD progression ending in End Stage Renal Disease. We propose to scientifically validate this model in in vitro experiments and create quantitative mathematical models for, inputs, outputs and their relationships to be implemented in Effectopedia.