Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish

Abstract

STATEMENTMortality associated with acute kidney injury (AKI) is in part due to limited treatments available to ameliorate kidney injury. We identified a compound that enhances AKI recovery by promoting cellular dedifferentiation. ABSTRACTAcute kidney injury (AKI) is a serious disorder for which there is no approved pharmaceutical treatment. Following injury, native nephrons display limited regenerative capabilities, relying on the dedifferentiation and proliferation of renal tubular epithelial cells (RTECs) that survive the insult. Previously, we identified 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor (HDI) that enhances renal recovery and showed that PTBA treatment increased RTEC proliferation and reduced renal fibrosis. Here, we investigated the regenerative mechanisms of PTBA in zebrafish models of larval renal injury and adult cardiac injury. With respect to renal injury, we showed that delivery of PTBA using an esterified prodrug (UPHD25) increases the reactivation of the renal progenitor gene Pax2a, enhances dedifferentiation of RTECs, reduces Kidney injury molecule-1 expression, and lowers the number of infiltrating macrophages. Further, we find that the effects of PTBA on RTEC proliferation depend upon retinoic acid signaling and demonstrate the therapeutic properties of PTBA are not restricted to the kidney but also increase cardiomyocyte proliferation and decrease fibrosis following cardiac injury in adult zebrafish.These studies provide key mechanistic insights into how PTBA enhances tissue repair in models of acute injury and lay the groundwork for translating this novel HDI into the clinic.

Somite morphogenesis is required for axial blood vessel formation during zebrafish embryogenesis

“…Three other methods of disrupting RA signaling caused the same phenotype. Loss of RA by treatment with N,Ndiethylaminobenzaldehyde (DEAB) (an inhibitor of the Aldh family, including Aldh1a2 (Morgan et al, 2015)), the small molecule retinoic acid receptor (RAR) alpha and gamma inhibitor (BMS453), or expression of a dominant negative RARa using the Tg(hsp70l:EGFP-dnHsa.RARA) transgenic line (hereafter referred to as HS:dnRAR) all caused midline migration defects (Skvarca et al, 2019) (Figure 1-figure supplement 1A-1E). Angioblasts in these embryos show delayed migration with disorganized anterior to posterior processivity.…”