Use of precision-cut renal cortical slices in nephrotoxicity studies

Abstract

1. Unlike cell lines and primary cells in culture, precision-cut tissue slices remain metabolically differentiated for at least 24–48 h and allow to study the effect of xenobiotics during short-term and long-term incubations.

2. In this article, we illustrate the use of such an experimental model to study the nephrotoxic effects of (i) chloroacetaldehyde, a metabolite of the anticancer drug ifosfamide, (ii) of cobalt chloride, a potential leakage product of the cobalt-containing nanoparticles, and (iii) of valproate, a widely used antiepileptic drug.

3. Since all the latter test compounds, like many toxic compounds, negatively interact with cellular metabolic pathways, we also illustrate our biochemical toxicology approach in which we used not only enzymatic but also carbon 13 NMR measurements and mathematical modelling of metabolic pathways.

4. This original approach, which can be applied to any tissue, allows to predict the nephrotoxic effects of milligram amounts of test compounds very early during the research and development processes of drugs and chemicals. This approach, combined with the use of cells that retain their in vivo metabolic properties and, therefore, are predictive, reduces the risk, the time and cost of such processes.

Keywords::

• Kidney
• toxicity
• metabolic pathways
• cellular metabolomics

Acknowledgements

The authors thank Remi Nazaret for technical assistance.

Declaration of interest

Gabriel Baverel is the founder of Metabolys Inc. and owns stock options of this company. Part of this work was supported by the European Community (STREP Project no. FP6-2004-NMP-TI-4-032731: CellNanoTox).