Acute kidney injury in zebrafish larvae as a regeneration model for drug discovery

Acute kidney injury (AKI) is a serious disorder for which there are limited clinical treatments. The Hukriede lab utilizes zebrafish as a screening model to identify small molecules that promote expansion of renal progenitor cells (RPCs) in the embryo, with the hypothesis that these compounds might also be effective AKI therapeutics by enhancing innate renal regenerative processes. This approach identified 4-(phenylthio)butanoic acid (PTBA), a novel class of histone deacetylase inhibitors (HDACi) that promotes RPC proliferation in zebrafish embryos by stimulating retinoic acid (RA) signaling. To evaluate the therapeutic potential of PTBA-class HDACi, we used a nephrotoxic model of gentamicin-induced AKI in zebrafish larvae that demonstrates the same hallmarks of renal injury and regeneration as the mammalian kidney. In this model, we show that m4PTB, the esterified version of PTBA, enhances post-AKI recovery by increasing dedifferentiation and proliferation of renal tubular epithelial cells (RTECs). To evaluate whether RA signaling also mediates m4PTB’s effects in this AKI model, we used Tg(12XRARE:EGFP) larvae to show that RA signaling increases rapidly after AKI, and that this response is critical for RTEC-dependent regeneration. Finally, we show that although m4PTB does not directly stimulate RA signaling in zebrafish larvae, blocking the RA pathway abrogates m4PTB’s effects on RTEC proliferation. These studies indicate that enhanced AKI recovery following m4PTB treatment requires intact RA signaling, and provide mechanistic insight into the signaling pathways involved in kidney regeneration post-AKI. Given the significant healthcare burden posed by AKI, these are critical initial steps in order to improve the treatment options available to patients.