An animal-free preclinical drug screening platform based on human precision-cut kidney slices

TY - JOUR

T1 - An animal-free preclinical drug screening platform based on human precision-cut kidney slices

AU - Mutsaers, Henricus A M

AU - Jensen, Michael Schou

AU - Kresse, Jean-Claude

AU - Tingskov, Stine Julie

AU - Madsen, Mia Gebauer

AU - Nørregaard, Rikke

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Animal Testing Alternatives

KW - Animals

KW - Drug Evaluation, Preclinical/methods

KW - Fibrosis

KW - Humans

KW - Kidney Diseases/drug therapy

KW - Kidney/pathology

KW - Renal Insufficiency, Chronic

KW - Transforming Growth Factor beta/genetics

UR - https://www.scopus.com/pages/publications/85150751365

U2 - 10.1186/s13104-023-06303-4

DO - 10.1186/s13104-023-06303-4

M3 - Journal article

C2 - 36941637

SN - 1756-0500

VL - 16

JO - BMC Research Notes

JF - BMC Research Notes

IS - 1

M1 - 39

ER -