Kidney Week

Abstract: SA-OR092

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

Session Information

• Transplantation: Back to the Basics
  October 27, 2018 | Location: 6D, San Diego Convention Center
  Abstract Time: 05:18 PM - 05:30 PM

Category: Transplantation

• 1801 Transplantation: Basic

Authors

• Concors, Seth, University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States

Seth Concors, MD



Dr. Seth Jason Concors completed his undergraduate training at New York University, and received his medical degree from New York University School of Medicine, where he graduated with Alpha Omega Alpha honors. Dr. Concors is currently a fifth-year general surgery resident. He is currently a Harrison Post-Doctoral Research Scholar in the laboratory of Dr. Matthew H. Levine, studying hepatic, renal and limb ischemia-reperfusion injury. He is additionally the clinical administrator of a Phase I/Phase II clinical trial with Dr. Levine examining the role of estrogen in improving renal transplantation outcomes. He has received the prestigious “Daland Fellowship in Clinical Investigation” from the American Philosophical Society, the oldest learned society in the United States, for his work with Dr. Levine. His research has resulted in multiple peer-reviewed publications and national presentations. Ultimately, Dr. Concors plans to pursue a career in academic surgical oncology, with a career focus on translational research, and clinical trials.

• Aufhauser, David Dean, University of Pennsylvania, Philadelphia, Pennsylvania, United States

David Dean Aufhauser,

• Wang, Zhonglin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Zhonglin Wang,

• Murken, Douglas R., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Douglas R. Murken,

• Ge, Guanghui, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Guanghui Ge,

• Bhatti, Tricia, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Tricia Bhatti,

• Hancock, Wayne W., Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, United States

Wayne W. Hancock,

• Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States

Matthew H. Levine,

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