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Abstract: SA-OR092

Histone Deacetylase-8 Inhibition Is Protective in Renal Ischemia-Reperfusion Injury

Session Information

Category: Transplantation

  • 1801 Transplantation: Basic

Authors

  • Concors, Seth, University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States
  • Aufhauser, David Dean, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Wang, Zhonglin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Murken, Douglas R., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ge, Guanghui, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Bhatti, Tricia, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Hancock, Wayne W., Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Ischemia/reperfusion injury (IRI) is a major source of morbidity in renal transplantation and other surgical scenarios, and has no specific therapy. In renal transplantation, IRI contributes to poor outcomes and early graft loss. Histone deacetylases (HDACs) regulate diverse cellular processes. We have previously shown that class I HDAC 1 and 2 have reciprocal effects on renal ischemia-reperfusion injury (IRI) with HDAC1 deletion increasing vulnerability and HDAC2 protection providing profound protection. HDAC8, another Class I HDAC, is structurally distinct from other members and is specifically targetable, making it a molecule of interest in IRI.

Methods

Whole-body tamoxifen-inducible HDAC -8 deficient (HDAC8 KO), and tamoxifen-treated WT female mice, as well as B6 female mice treated with specific HDAC8 inhibitor (OJ-1) or DMSO control were used. Mice were subjected to warm renal IRI through unilateral clamping of the renal pedicle and contralateral nephrectomy under strict temperature control. Creatinine and BUN were examined at 24-, 48-, 72-, and 96-h post IRI.

Results

HDAC8 KO (Figure 1A& 1B) and inhibitor-treated (Figure 1C & 1D) mice developed significantly less renal injury after renal IRI than controls, with significantly decreased post-operative BUN and Cr (p<0.0001 for all).

Conclusion

HDAC8 knockout and pharmacologic inhibition appears to be proactive in a standard model of renal warm IRI. The benefit of short term HDAC8 pharmacologic inhibition represents an important finding, demonstrating highly novel translational potential. Further clinical correlation and mechanistic understanding is needed for this candidate molecule.

Funding

  • NIDDK Support