ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0331

Pharmacological Validation of HDAC8 as a Therapeutic Target for AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Huryn, Donna M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Long, Keith E., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • McDaniels, Michael D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Delgado, Rachel, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Vaughn, Zoe, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Iyer, Prema C., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Sander, Veronika, The University of Auckland, Auckland, Auckland, New Zealand
  • Davidson, Alan J., The University of Auckland, Auckland, Auckland, New Zealand
  • de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Hukriede, Neil A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Background

Treatment for acute kidney injury (AKI) remains a significant unmet medical need and there are few validated targets on which to base therapeutic interventions and drug discovery programs. Our work has revealed histone deacetylase 8 (HDAC8) as a promising new candidate.

Methods

Known potent, selective HDAC8 inhibitors, as well as negative control compounds within the same scaffold, were evaluated in gentamicin-induced AKI in zebrafish (zfAKI), reperfusion injury AKI (IRI-AKI) in mouse, and in human kidney organoid-derived tubule cells subjected to hypoxia.

Results

Known potent, selective HDAC8 inhibitors such as PCI-34051, tetrahydroisoquinoline hydroxamic acids and an isoindolyl amide were effective in the zf AKI assays, while control compounds (i.e. HDAC8 inactive compounds of the same scaffold) were not effective. Testing of PCI-34051 in the IRI-AKI mouse model showed improvements in kidney function markers (BUN, tGFR) and while there was no significant reduction in renal fibrosis as measured by Sirius red staining, expression of the renal fibrosis markers Collagen 1a1 and LoxL2 were reduced. Further evaluation of PCI-34051 and the isoindolyl amide in primary renal epithelial cells from human kidney organoids showed that HDAC8 inhibition is associated with a pronounced suppression of inflammatory cytokine genes, providing one mechanism to explain their in vivo efficacy.

Conclusion

Our data supports that pharmacological inhibition of HDAC8 ameliorates AKI injury in multiple in vivo models and validates this target as a promising therapeutic lead to treat AKI.

Funding

  • NIDDK Support