Histone Deacetylases Cooperate with NF-κB to Support the Immediate Migratory Response after Zebrafish Pronephros Injury

Int J Mol Sci. 2022 Aug 24;23(17):9582. doi: 10.3390/ijms23179582.


Acute kidney injury (AKI) is commonly associated with severe human diseases, and often worsens the outcome in hospitalized patients. The mammalian kidney has the ability to recover spontaneously from AKI; however, little progress has been made in the development of supportive treatments. Increasing evidence suggest that histone deacetylases (HDAC) and NF-κB promote the pathogenesis of AKI, and inhibition of Hdac activity has a protective effect in murine models of AKI. However, the role of HDAC at the early stages of recovery is unknown. We used the zebrafish pronephros model to study the role of epigenetic modifiers in the immediate repair response after injury to the tubular epithelium. Using specific inhibitors, we found that the histone deacetylase Hdac2, Hdac6, and Hdac8 activities are required for the repair via collective cell migration. We found that hdac6, hdac8, and nfkbiaa expression levels were upregulated in the repairing epithelial cells shortly after injury. Depletion of hdac6, hdac8, or nfkbiaa with morpholino oligonucleotides impaired the repair process, whereas the combined depletion of all three genes synergistically suppressed the recovery process. Furthermore, time-lapse video microscopy revealed that the lamellipodia and filopodia formation in the flanking cells was strongly reduced in hdac6-depleted embryos. Our findings suggest that Hdac activity and NF-κB are synergistically required for the immediate repair response in the zebrafish pronephros model of AKI, and the timing of HDAC inhibition might be important in developing supportive protocols in the human disease.

Keywords: HDAC; acute kidney injury; directed cell migration; epigenetic modifiers; histone deacetylase; laser ablation; zebrafish pronephros.

MeSH terms

  • Acute Kidney Injury* / genetics
  • Acute Kidney Injury* / pathology
  • Animals
  • Histone Deacetylase 6 / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / metabolism*
  • Humans
  • Mice
  • NF-kappa B
  • Pronephros* / metabolism
  • Pronephros* / pathology
  • Repressor Proteins
  • Zebrafish / metabolism
  • Zebrafish Proteins / metabolism*


  • HDAC8 protein, zebrafish
  • Histone Deacetylase Inhibitors
  • NF-kappa B
  • Repressor Proteins
  • Zebrafish Proteins
  • HDAC6 protein, zebrafish
  • Histone Deacetylase 6
  • Histone Deacetylases