Implementation of a human renal proximal tubule on a chip for nephrotoxicity and drug interaction studies
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Autor:innen
Hutter, Simon
Vormann, Marianne
Vriend, Jelle
Lanz, Henriette
Gijzen, Linda
van den Heuvel, Angelique
Joore, Jos
Trietsch, Sebastian
Autor:in (Körperschaft)
Publikationsdatum
04.04.2021
Typ der Arbeit
Studiengang
Typ
01A - Beitrag in wissenschaftlicher Zeitschrift
Herausgeber:innen
Herausgeber:in (Körperschaft)
Betreuer:in
Übergeordnetes Werk
Journal of Pharmaceutical Sciences
Themenheft
DOI der Originalpublikation
Link
Reihe / Serie
Reihennummer
Jahrgang / Band
110
Ausgabe / Nummer
4
Seiten / Dauer
1601-1614
Patentnummer
Verlag / Herausgebende Institution
Elsevier
Verlagsort / Veranstaltungsort
Auflage
Version
Programmiersprache
Abtretungsempfänger:in
Praxispartner:in/Auftraggeber:in
Zusammenfassung
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).
Schlagwörter
Renal-proximal-tubule-on-a-chip, Drug-screening, Drug-transporter interaction, miRNA, Microfluidics, Pharmaceutical
Fachgebiet (DDC)
Veranstaltung
Startdatum der Ausstellung
Enddatum der Ausstellung
Startdatum der Konferenz
Enddatum der Konferenz
Datum der letzten Prüfung
ISBN
ISSN
0022-3549
1520-6017
1520-6017
Sprache
Englisch
Während FHNW Zugehörigkeit erstellt
Ja
Zukunftsfelder FHNW
Publikationsstatus
Veröffentlicht
Begutachtung
Peer-Review der ganzen Publikation
Open Access-Status
Hybrid
Lizenz
Zitation
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