Development of an in vitro renal epithelial disease state model for xenobiotic toxicity testing

Daniel Crean, Patricia Bellwon, Lydia Aschauer, Alice Limonciel, Konrad Moenks, Philip Hewitt, Tobias Schmidt, Karin Herrgen, Wolfgang Dekant, Arno Lukas, Frederic Bois, Anja Wilmes, Paul Jennings, Martin Leonard*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

There is a growing impetus to develop more accurate, predictive and relevant in vitro models of renal xenobiotic exposure. As part of the EU-FP7, Predict-IV project, a major aim was to develop models that recapitulate not only normal tissue physiology but also aspects of disease conditions that exist as predisposing risk factors for xenobiotic toxicity. Hypoxia, as a common micro-environmental alteration associated with pathophysiology in renal disease, was investigated for its effect on the toxicity profile of a panel of 14 nephrotoxins, using the human proximal tubular epithelial RPTECT/TERT1 cell line. Changes in ATP, glutathione and resazurin reduction, after 14 days of daily repeat exposure, revealed a number of compounds, including adefovir dipivoxil with enhanced toxicity in hypoxia. We observed intracellular accumulation of adefovir in hypoxia and suggest decreases in the efflux transport proteins MRP4, MRP5, NHERF1 and NHERF3 as a possible explanation. MRP5 and NHERF3 were also down-regulated upon treatment with the HIF-1 activator, dimethyloxalylglycine. Interestingly, adefovir dependent gene expression shifted from alterations in cell cycle gene expression to an inflammatory response in hypoxia. The ability to investigate aspects of disease states and their influence on renal toxin handling is a key advantage of in vitro systems developed here. They also allow for detailed investigations into mechanisms of compound toxicity of potential importance for compromised tissue exposure.

Original languageEnglish
Pages (from-to)128-137
Number of pages10
JournalToxicology in Vitro
Volume30
Issue number1
DOIs
Publication statusPublished - 25 Dec 2015

Bibliographical note

Funding Information:
We would like to thank Hannelore Popa-Henning for her contribution the Predict-IV project. This project was funded by the European Union’s 7th Framework Programme (FP7/2007-2013) under Grant agreement no. 202222, Predict-IV. The funding agency had no input into study design and in the decision to publish.

Publisher Copyright:
© 2014 Elsevier Ltd.

Keywords

  • Chronic kidney disease
  • Hypoxia
  • Nephrotoxicity
  • Proximal tubule

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