Abstract: PO0331
Pharmacological Validation of HDAC8 as a Therapeutic Target for AKI
Session Information
- AKI: Mechanisms of Injury
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
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