Implementation of a human renal proximal tubule on a chip for nephrotoxicity and drug interaction studies
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Authors
Hutter, Simon
Vormann, Marianne
Vriend, Jelle
Lanz, Henriette
Gijzen, Linda
van den Heuvel, Angelique
Joore, Jos
Trietsch, Sebastian
Author (Corporation)
Publication date
04.04.2021
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Type
01A - Journal article
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Parent work
Journal of Pharmaceutical Sciences
Special issue
DOI of the original publication
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Series number
Volume
110
Issue / Number
4
Pages / Duration
1601-1614
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Publisher / Publishing institution
Elsevier
Place of publication / Event location
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Abstract
Proximal tubule epithelial cells (PTEC) are susceptible to drug-induced kidney injury (DIKI). Cell-based, two-dimensional (2D) in vitro PTEC models are often poor predictors of DIKI, probably due to the lack of physiological architecture and flow. Here, we assessed a high throughput, 3D microfluidic platform (Nephroscreen) for the detection of DIKI in pharmaceutical development. This system was established with four model nephrotoxic drugs (cisplatin, tenofovir, tobramycin and cyclosporin A) and tested with eight pharmaceutical compounds. Measured parameters included cell viability, release of lactate dehydrogenase (LDH) and N-acetyl-β-d-glucosaminidase (NAG), barrier integrity, release of specific miRNAs, and gene expression of toxicity markers. Drug-transporter interactions for P-gp and MRP2/4 were also determined. The most predictive read outs for DIKI were a combination of cell viability, LDH and miRNA release. In conclusion, Nephroscreen detected DIKI in a robust manner, is compatible with automated pipetting, proved to be amenable to long-term experiments, and was easily transferred between laboratories. This proof-of-concept-study demonstrated the usability and reproducibility of Nephroscreen for the detection of DIKI and drug-transporter interactions. Nephroscreen it represents a valuable tool towards replacing animal testing and supporting the 3Rs (Reduce, Refine and Replace animal experimentation).
Keywords
Renal-proximal-tubule-on-a-chip, Drug-screening, Drug-transporter interaction, miRNA, Microfluidics, Pharmaceutical
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ISBN
ISSN
0022-3549
1520-6017
1520-6017
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Hybrid
License
Citation
Suter-Dick, L., Caj, M., Hutter, S., Vormann, M., Vriend, J., Lanz, H., Gijzen, L., van den Heuvel, A., Joore, J., Trietsch, S., Stuut, C., Nieskens, T. T. G., Peters, J., Ramp, D., Russel, F., Roth, A., Lu, S., Polli, J., & Jacobsen, B. (2021). Implementation of a human renal proximal tubule on a chip for nephrotoxicity and drug interaction studies. Journal of Pharmaceutical Sciences, 110(4), 1601–1614. https://doi.org/10.1016/j.xphs.2021.01.028