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An animal-free preclinical drug screening platform based on human precision-cut kidney slices
Henricus A M Mutsaers1, Michael Schou Jensen2, Jean-Claude Kresse2
1Department of Clinical Medicine, Aarhus University, Palle Juul-Jensens Boulevard 99, Aarhus N, 8200, Denmark. h.a.m.mutsaers@clin.au.dk.
Objective:
Renal fibrosis is one of the main pathophysiological processes underlying the progression of chronic kidney disease and kidney allograft failure. In the past decades, overwhelming efforts have been undertaken to find druggable targets for the treatment of renal fibrosis, mainly using cell- and animal models. However, the latter often do not adequately reflect human pathogenesis, obtained results differ per strain within a given species, and the models are associated with considerable discomfort for the animals. Therefore, the objective of this study is to implement the 3Rs in renal fibrosis research by establishing an animal-free drug screening platform for renal fibrosis based on human precision-cut kidney slices (PCKS) and by limiting the use of reagents that are associated with significant animal welfare concerns.
Results:
Using Western blotting and gene expression arrays, we show that transforming growth factor-β (TGF-β) induced fibrosis in human PCKS. In addition, our results demonstrated that butaprost, SC-19220 and tamoxifen - all putative anti-fibrotic compounds - altered TGF-β-induced pro-fibrotic gene expression in human PCKS. Moreover, we observed that all compounds modulated fairly distinct sets of genes, however they all impacted TGF-β/SMAD signaling. In conclusion, this study revealed that it is feasible to use an animal-free approach to test drug efficacy and elucidate mechanisms of action.
Insights
This study introduces an animal-free drug screening platform for renal fibrosis using human kidney slices. The platform successfully identified anti-fibrotic compounds, demonstrating a viable alternative to animal testing.
Area of Science:
- Nephrology
- Pharmacology
- Translational Medicine
Background:
- Renal fibrosis drives chronic kidney disease and transplant failure.
- Current drug discovery relies on animal models with limitations in human relevance and animal welfare.
- There is a need for 3Rs-compliant (Replacement, Reduction, Refinement) research methods.
Purpose of the Study:
- To establish an animal-free drug screening platform for renal fibrosis.
- To implement the 3Rs in kidney disease research.
- To test the efficacy of potential anti-fibrotic compounds using human precision-cut kidney slices (PCKS).
Main Methods:
- Utilized human precision-cut kidney slices (PCKS) as an in vitro model.
- Induced fibrosis in PCKS using transforming growth factor-β (TGF-β).
- Analyzed drug effects on gene expression and TGF-β/SMAD signaling via Western blotting and gene expression arrays.
Main Results:
- TGF-β successfully induced fibrosis in human PCKS.
- Putative anti-fibrotic compounds (butaprost, SC-19220, tamoxifen) modulated TGF-β-induced pro-fibrotic gene expression.
- All tested compounds impacted the TGF-β/SMAD signaling pathway, though they affected distinct gene sets.
Conclusions:
- An animal-free approach using human PCKS is feasible for drug screening in renal fibrosis.
- This method allows for the evaluation of drug efficacy and elucidation of mechanisms of action.
- The platform supports the 3Rs by reducing reliance on animal models and potentially harmful reagents.
