Predictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis

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 o...

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Published in:Pharmaceutics 2020-05, Vol.12 (5), p.459
Main Authors: Bigaeva, Emilia, Puerta Cavanzo, Nataly, Stribos, Elisabeth G D, de Jong, Amos J, Biel, Carin, Mutsaers, Henricus A M, Jensen, Michael S, Nørregaard, Rikke, Leliveld, Anna M, de Jong, Igle J, Hillebrands, Jan-Luuk, van Goor, Harry, Boersema, Miriam, Bank, Ruud A, Olinga, Peter
Format: Article
Language:English
Subjects:
Adenosine triphosphate
Animals
antifibrotic drugs
Fibroblasts
galunisertib
Growth factors
imatinib
Kidney diseases
pirfenidone
precision-cut kidney slices
renal fibrosis
Studies
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Summary: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.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics12050459