D. Murken1, D. Aufhauser1, Z. Wang1, G. Ge1, T. Bhatti3, W. Hancock3, M. Levine1,2 1University Of Pennsylvania,Department Of Surgery,Philadelphia, PA, USA 2Children’s Hospital Of Philadelphia,Department Of Surgery,Philadelphia, PA, USA 3Children’s Hospital Of Philadelphia,Department Of Pathology And Laboratory Medicine,Philadelphia, PA, USA
Introduction: Ischemia Reperfusion Injury (IRI) causes significant morbidity in renal transplantation and other surgical scenarios. A better understanding of the molecular mechanisms leading to IRI is required so that new strategies for prevention and treatment can be developed. Histone deacetylases (HDACs) regulate diverse cellular processes. We have previously shown the benefit in renal IRI of non-selective pharmacologic HDAC inhibitors, and now report on the benefit of targeting one specific HDAC isoform, HDAC2, via inducible whole body gene deletion in order to extend renal IRI tolerance.
Methods: Female wild type C57BL/6 (WT) or female whole body HDAC2-deficient C57BL/6 (HDAC2-/-) mice were subjected to a unilateral warm ischemia model with contralateral nephrectomy under strict temperature control in order to yield maximum reproducibility. Plasma concentrations of BUN were assessed for four days post-operatively.
Results: WT mice survived 28 minutes of warm ischemic time, but developed substantial injury (Figure 1). When subjected to longer periods of warm ischemia, these mice all developed renal insufficiency requiring sacrifice within 48 hours of ischemic insult. HDAC2-/- mice were subjected to longer periods of warm ischemia than survivable by WT mice. HDAC2-/- mice tolerated 35 minutes of ischemia with comparable renal injury to that observed in WT mice after 28 minutes of IRI (p=0.48, Figure 1). Prolongation of the ischemic time by a further two additional minutes (37 min) resulted in non-survivable injury in HDAC2-/- mice.
Conclusion: Murine HDAC2 gene deletion leads to significant extension of renal IRI tolerance. Pharmacologic HDAC2 inhibition may offer a novel therapeutic strategy to avoid organ injury in kidney transplantation and other surgeries requiring renal ischemia.
