Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules
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Autor:innen
Vormann, Marianne K.
Gijzen, Linda
Hutter, Simon
Boot, Lisette
Nicolas, Arnaud
van den Heuvel, Angelique
Vriend, Jelle
Ng, Chee Ping
Nieskens, Tom T.G.
van Duinen, Vincent
Autor:in (Körperschaft)
Publikationsdatum
08/2018
Typ der Arbeit
Studiengang
Typ
01 - Zeitschriftenartikel, Journalartikel oder Magazin
Herausgeber:innen
Herausgeber:in (Körperschaft)
Betreuer:in
Übergeordnetes Werk
The AAPS Journal
Themenheft
DOI der Originalpublikation
Reihe / Serie
Reihennummer
Jahrgang / Band
20
Ausgabe / Nummer
5
Seiten / Dauer
90
Patentnummer
Verlag / Herausgebende Institution
Verlagsort / Veranstaltungsort
Auflage
Version
Programmiersprache
Abtretungsempfänger:in
Praxispartner:in/Auftraggeber:in
Zusammenfassung
Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.
Schlagwörter
kidney-on-a-chip, nephrotoxiciy, apparent permeability (Papp), Proximal tubule, transepithelial transport
Fachgebiet (DDC)
Veranstaltung
Startdatum der Ausstellung
Enddatum der Ausstellung
Startdatum der Konferenz
Enddatum der Konferenz
Datum der letzten Prüfung
ISBN
ISSN
Sprache
Englisch
Während FHNW Zugehörigkeit erstellt
Ja
Publikationsstatus
Veröffentlicht
Begutachtung
Peer-Review der ganzen Publikation
Open Access-Status
Lizenz
Zitation
VORMANN, Marianne K., Linda GIJZEN, Simon HUTTER, Lisette BOOT, Arnaud NICOLAS, Angelique VAN DEN HEUVEL, Jelle VRIEND, Chee Ping NG, Tom T.G. NIESKENS, Vincent VAN DUINEN, Bjorn DE WAGENAAR, Rosalinde MASEREEUW, Laura SUTER-DICK, Sebastian J. TRIETSCH, Martijn WILMER, Jos JOORE, Paul VULTO und Henriette LANZ, 2018. Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules. The AAPS Journal. August 2018. Bd. 20, Nr. 5, S. 90. DOI 10.1208/s12248-018-0248-z. Verfügbar unter: http://hdl.handle.net/11654/26951