PUBLICATION

Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish

Authors
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.
ID
ZDB-PUB-190321-6
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
Datasets
GEO:GSE126418
MeSH Terms
  • Sulfides/pharmacology*
  • Cell Proliferation/drug effects
  • Kidney Tubules/pathology
  • Acute Kidney Injury/pathology*
  • Acute Kidney Injury/physiopathology*
  • Animals
  • Immune System/drug effects
  • Immune System/metabolism
  • Macrophages/drug effects
  • Macrophages/metabolism
  • Regeneration*
  • Neutrophils/drug effects
  • Neutrophils/metabolism
  • Epithelial Cells/drug effects
  • Epithelial Cells/pathology
  • Signal Transduction/drug effects
  • Zebrafish Proteins/metabolism
  • Tretinoin/pharmacology
  • Cell Dedifferentiation*/drug effects
  • Butyrates/pharmacology*
  • Prodrugs/pharmacology
  • Zebrafish/immunology
  • Zebrafish/physiology*
  • Animals, Genetically Modified
  • PAX2 Transcription Factor/metabolism
(all 25)
PubMed
30890583 Full text @ Dis. Model. Mech.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Human Disease Fish Conditions Evidence
kidney diseaseABchemical treatment by injection: gentamycinTAS
1 - 1 of 1
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Sequence Targeting Reagents
No data available
Fish
Fish
AB
ci1008Tg
nz4Tg
nz4Tg; uwm12Tg
nz117Tg
nz117Tg; pt307Tg
pt307Tg; uwm12Tg
1 - 7 of 7
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Antibodies
Orthology
No data available
Engineered Foreign Genes
Marker Marker Type Name
Dendra2EFGDendra2
EGFPEFGEGFP
mCherryEFGmCherry
1 - 3 of 3
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Mapping
No data available
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Citation
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. (2019) Enhancing acute kidney injury regeneration by promoting cellular dedifferentiation in zebrafish. Disease models & mechanisms. 12(4):.