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Abstract: SA-OR15

Genetic Validation of Hdac8 as a Therapeutic Target for AKI

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hukriede, Neil A., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • Delgado, Rachel, Vanderbilt University Medical Center, Nashville, Tennessee, United States
  • Przepiorski, Aneta J., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • McDaniels, Michael D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
  • de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background

We previously identified 4-phenylthiobutanoic acid (PTBA), which enhances repair in multiple models of AKI, and showed that histone deacetylase 8 (Hdac8) is a target of PTBA. Here, we show that loss of genetic deletion of Hdac8 protects against AKI in zebrafish, human kidney organoid and mouse models, and that Hdac8 mediates the efficacy of PTBA.

Methods

hdac8sa14948/- and wild type zebrafish were injected with gentamicin to induce AKI, treated +/- the PTBA prodrug, UPHD25, and AKI severity evaluated by survival, tubular proliferation, DNA damage response, and apoptosis with EdU, γH2AX, and TUNEL staining, respectively. Tamoxifen treated male UB-CRERT2; Hdac8Y/LoxP (Hdac8 KO) were evaluated over 28 days after severe ischemia reperfusion AKI (IR-AKI) by transdermal GFR (tGFR) and Sirius red staining for fibrosis. Hemin treated Hdac8 KO human kidney organoids were evaluated for injury and inflammatory markers.

Results

hdac8-/- zebrafish had enhanced survival after AKI compared to wild type controls associated with increased tubular cell proliferation, γH2AX expression, and reduced apoptosis. There was no improvement in survival in hdac8+/- mutant zebrafish with AKI, but when hdac8+/- mutants were treated with sub-therapeutic doses of UPHD25, they had improved survival. In mice, Hdac8 KO had increased tGFR at day 28 (CRE- vs. +, 495.1 (46.6) vs. 704.2 (77.1) ml/min/100gm, p<0.05), associated with reduced fibrosis in the outer medulla, and organoids showed a suppression of inflammatory markers.

Conclusion

Loss of Hdac8 reduced severity of injury and improves repair in models of AKI. Studies in Hdac8+/- mutants using sub-therapeutic doses of UPHD25 indicate that PTBA efficacy is mediated in AKI via Hdac8. Increased γH2AX expression with reduced apoptosis after AKI suggests that hdac8-/- null zebrafish preferentially uses mechanisms of DDR for repair. These data provide strong genetic evidence that Hdac8 is a valid therapeutic target for AKI; mediates PTBA effects; and suggest a potential mechanism by which Hdac8 deletion induces productive repair.

Funding

  • NIDDK Support