HDAC2 Deletion Leads to Increased Tolerance of Renal Ischemia Reperfusion Injury.

Abstract

Introduction: We have shown the pan-HDAC drug inhibition leads to increased renal ischemia reprerfusion (IRI) tolerance in terms of early graft function and fibrosis formation long term and that the majority of these effects can be reproduced with class I HDAC drug inhibitors. We sought to determine which HDAC member is responsible. Methods: A murine model renal IRI with female mice undergoing 28 minutes of unilateral warm ischemia and contralateral nephrectomy was undertaken in mice with inducible deletion under the ERT2-Cre of floxed HDAC1 and 2. Pan-HDAC3 deletion led to murine death so kidney specific deletion was achieved by transplanting floxed HDAC3:ERT2-Cre kidneys into normal mice and then performing IRI after the transplant had stabilized with normal controls as comparison. Renal function for 4 consecutive days was measured by BUN and fibrosis scoring was performed by automated Sirius Red staining at 30d after injury. Results: We determined that HDAC2 whole animal deletion led to substantial improvement in IRI tolerance - in fact much greater than attained with panHDAC (TSA) or class I specific HDAC (MS275) drug inhibitors as determined by serial BUN measurement (Fig 1).Figure: No Caption available.HDAC2 pan-deletion was associated with significant diminution of fibrosis at 30 days relative to wildtype. HDAC1 pan-deletion was well tolerated and induced moderate worsening of IRI tolerance with no significant change in renal fibrosis at 30 days. HDAC3 pandeletion was lethal at a mean of 17 days. HDAC3 deletion isolated to the kidney led to modest improvement in renal IRI compared to wild type control but this did not reach significance. HDAC3 renal deletion did not have significant impact on fibrosis at 30 days. Conclusion: HDAC2 deletion leads to substantial improvement in renal IRI tolerance and diminution of fibrosis formation after renal IRI. HDAC1 deletion is modestly detrimental to renal IRI tolerance. HDAC3 pan-deletion is lethal and at best modestly improves renal IRI tolerance when confined to the kidney.