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Archives of Toxicology

, Volume 93, Issue 7, pp 1965–1978 | Cite as

Functional transepithelial transport measurements to detect nephrotoxicity in vitro using the RPTEC/TERT1 cell line

  • Philipp F. Secker
  • Nadja Schlichenmaier
  • Mario Beilmann
  • Ulrich Deschl
  • Daniel R. DietrichEmail author
Organ Toxicity and Mechanisms
  • 367 Downloads

Abstract

The kidney is a frequent target for organ-specific toxicity as a result of its primary function in controlling body fluids, for example, via resorption of amino acids, peptides, nutrients, ions, xenobiotics and water from the primary urine as well as excretion of metabolic waste products and hydrophilic and amphiphilic xenobiotics. Compounds exhibiting dose-limiting nephrotoxicity include drugs from highly diverse classes and chemical structures, e.g., antibiotics (gentamicin), chemotherapeutics (cisplatin), immunosuppressants (cyclosporine A and tacrolimus) or bisphosphonates (zoledronate). All of these compounds elicit nephrotoxicity primarily by injuring renal proximal tubule epithelial cells (RPTECs). However, prediction of a compound’s nephrotoxic potential in humans to support early unmasking of risk-bearing drug candidates remains an unmet challenge, mainly due to the complex kidney anatomy as well as pronounced inter- and intraspecies differences and lack of relevant and validated human in vitro models. Accordingly, we used the recently established human RPTEC/TERT1 cell line to carry out toxicity studies with a focus on impairment of functional characteristics, i.e., transepithelial electrical resistance (TEER), vectorial transport of water, cations, and anions. Results were compared to real-time cytotoxicity assessments using cellular impedance (xCELLigence assay) and the routine cell viability readout (MTT). As expected, most toxins caused exposure time- and concentration-dependent cytotoxicity. However, for some compounds (cyclosporine A and tacrolimus), transport processes were strongly impaired in absence of a concomitant decrease in cell viability. In conclusion, these data demonstrate that functional parameters are important, highly sensitive and meaningful additional readouts for nephrotoxicity assessment in human renal proximal tubule epithelial cells.

Keywords

Kidney Nephrotoxicity Proximal tubule In vitro Epithelial transport 

Notes

Supplementary material

204_2019_2469_MOESM1_ESM.docx (15 kb)
Supplementary file1 (DOCX 14 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Human and Environmental Toxicology, Department of BiologyUniversity of KonstanzKonstanzGermany
  2. 2.Brain Cancer Metabolism GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Boehringer Ingelheim Pharma GmbH & Co. KG, Non-Clinical Drug SafetyBiberachGermany

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