ZFIN ID: ZDB-PUB-190321-6
Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish
Skvarca, L.B., Han, H.I., Espiritu, E.B., Missinato, M.A., Rochon, E.R., McDaniels, M.D., Bais, A.S., Roman, B.L., Waxman, J.S., Watkins, S.C., Davidson, A.J., Tsang, M., Hukriede, N.A.
Date: 2019
Source: Disease models & mechanisms   12(4): (Journal)
Registered Authors: Hukriede, Neil, Roman, Beth, Tsang, Michael, Waxman, Joshua
Keywords: Acute kidney injury, Cardiovascular, HDAC inhibitor, Macrophages, Renal proximal tubule cell, Therapeutic
Microarrays: GEO:GSE126418
MeSH Terms:
  • Acute Kidney Injury/pathology*
  • Acute Kidney Injury/physiopathology*
  • Animals
  • Animals, Genetically Modified
  • Butyrates/pharmacology*
  • Cell Dedifferentiation*/drug effects
  • Cell Proliferation/drug effects
  • Epithelial Cells/drug effects
  • Epithelial Cells/pathology
  • Immune System/drug effects
  • Immune System/metabolism
  • Kidney Tubules/pathology
  • Macrophages/drug effects
  • Macrophages/metabolism
  • Neutrophils/drug effects
  • Neutrophils/metabolism
  • PAX2 Transcription Factor/metabolism
  • Prodrugs/pharmacology
  • Regeneration*
  • Signal Transduction/drug effects
  • Sulfides/pharmacology*
  • Tretinoin/pharmacology
  • Zebrafish/immunology
  • Zebrafish/physiology*
  • Zebrafish Proteins/metabolism
PubMed: 30890583 Full text @ Dis. Model. Mech.
Acute kidney injury (AKI) is a serious disorder for which there are limited treatment options. 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 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.