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Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):128-37. doi: 10.1016/j.tiv.2014.11.015. Epub 2014 Dec 20.

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

Author information

1
University College Dublin, School of Medicine and Medical Science, Dublin, Ireland.
2
Institut fuer Toxikologie, Universitaet Wuerzburg, Versbacher Str. 9, 97078 Würzburg, Germany.
3
Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck 6020, Austria.
4
Emergentec Biodevelopment GmbH, Vienna 1180, Austria.
5
Merck KGaA, Merck Serono, Nonclinical Safety, Darmstadt 64293, Germany.
6
Université de Technologie de Compiègne, Compiègne Cedex 60205, France.
7
Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot OX11 0RQ, UK. Electronic address: Martin.Leonard@phe.gov.uk.

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.

KEYWORDS:

Chronic kidney disease; Hypoxia; Nephrotoxicity; Proximal tubule

PMID:
25536518
DOI:
10.1016/j.tiv.2014.11.015
[Indexed for MEDLINE]

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