RT Journal Article
SR Electronic
T1 Recellularized Native Kidney Scaffolds as a Novel Tool in Nephrotoxicity Screening
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1338
OP 1350
DO 10.1124/dmd.118.080721
VO 46
IS 9
A1 Michele Fedecostante
A1 Koen G. C. Westphal
A1 Michele F. Buono
A1 Natalia Sanchez Romero
A1 Martijn J. Wilmer
A1 Janis Kerkering
A1 Pedro Miguel Baptista
A1 Joost G. Hoenderop
A1 Rosalinde Masereeuw
YR 2018
UL http://dmd.aspetjournals.org/content/46/9/1338.abstract
AB Drug-induced kidney injury in medicinal compound development accounts for over 20% of clinical trial failures and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity; neither are such models easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform on the basis of decellularized rat kidney scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC–OAT1). A 5-day SDS-based decellularization protocol was used to generate DS, of which 100-μm slices were cut and used for cell seeding. After 8 days of culturing, recellularized scaffolds (RS) demonstrated 3D-tubule formation along with tubular epithelial characteristics, including drug transporter function. Exposure of RS to cisplatin (CDDP), tenofovir (TFV), or cyclosporin A (CsA) as prototypical nephrotoxic drugs revealed concentration-dependent reduction in cell viability, as assessed by PrestoBlue and Live/Dead staining assays. This was most probably attributable to specific uptake of CDDP by the organic cation transporter 2 (OCT2), TFV through organic anion transporter 1 (OAT1), and CsA competing for P-glycoprotein-mediated efflux. Compared with 2D cultures, RS showed an increased sensitivity to cisplatin and tenofovir toxicity after 24-hour exposure (9 and 2.2 fold, respectively). In conclusion, we developed a physiologically relevant 3D nephrotoxicity screening platform that could be a novel tool in drug development.