Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis
Emilia Bigaeva,
Nataly Puerta Cavanzo,
Elisabeth G. D. Stribos,
Amos J. de Jong,
Carin Biel,
Henricus A. M. Mutsaers,
Michael S. Jensen,
Rikke Nørregaard,
Anna M. Leliveld,
Igle J. de Jong,
Jan-Luuk Hillebrands,
Harry van Goor,
Miriam Boersema,
Ruud A. Bank,
Peter Olinga
Affiliations
Emilia Bigaeva
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Nataly Puerta Cavanzo
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Elisabeth G. D. Stribos
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Amos J. de Jong
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Carin Biel
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Henricus A. M. Mutsaers
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Michael S. Jensen
Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
Rikke Nørregaard
Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
Anna M. Leliveld
Department of Urology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Igle J. de Jong
Department of Urology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Jan-Luuk Hillebrands
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Harry van Goor
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Miriam Boersema
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Ruud A. Bank
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
Peter Olinga
Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen Research Institute of Pharmacy, 9713 AV Groningen, The Netherlands
Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGFβ or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation; (2) expression of markers of TGFβ and PDGF signaling; and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponded with the known in vivo responses observed in various animal models of renal fibrosis. Moreover, our results suggested that human PCKS can be used to predict drug efficacy in clinical trials. In conclusion, our study demonstrated that the PCKS model is a powerful predictive tool for ex vivo screening of putative drugs for renal fibrosis.
