Population genetics meets precision-cut kidney slices: Nephrotoxicity modelled ex vivo in the founder strains of the BXD mouse consortium

Acute kidney injury (AKI) affects millions of patients annually and is associated with high morbidity and mortality, to date no curative treatment exists. Drug-induced nephrotoxicity accounts for up to 25% of AKI cases, but individual susceptibility remains hard to predict. While genetic factors are suspected to play a part in this variability, the pharmacogenomics of nephrotoxin-induced kidney injury remain largely unknown. To investigate genetically determined susceptibility, we used precision-cut kidney slices (PCKS) from the two founder strains of the BXD mouse consortium, C57BL/6J and DBA/2J. PCKS preserves tissue architecture and cell-cell interaction, allowing close experimental control while maintaining the renal microenvironment. Slices were exposed to cyclosporine A (80 nM for 6h, 20nM for 24h and 48h) and Tunicamycin (1 {micro}M for 6h and for 24h) as well as normoxia (4{degrees}C for 20h) and hyperoxia (4{degrees}C for 20h and 4h in incubator). Slices were then analysed using histopathological scoring, TUNEL staining, ATP quantification and bulk RNA sequencing. We found that the main source of variation was experimental duration. Nevertheless, a subtle difference between the strains could be observed for both cyclosporine A and Tunicamycin, with DBA/2J showing a stronger response to nephrotoxic stress, including lower ATP levels, higher proportion of apoptotic cells and a more pronounced transcriptomic response. For both strains, normoxia was the least harmful condition. These findings support the hypothesis that the BXD founder strains differ in their susceptibility to nephrotoxic kidney injury and support the use of PCKS as a relevant ex vivo model for studying early renal stress response. This provides the foundation to extend this approach to a broader spectrum of the BXD population to identify genetic loci and candidate genes involved in genetic susceptibility to nephrotoxins.