Introduction: Histone/protein deacetylases (HDACs) regulate gene expression by modifying chromatin accessibility and protein acetylation. We have previously found that deletion of HDAC2 protects from renal ischemia-reperfusion injury (IRI) and wished both to determine the tissue specificity of the HDAC2 deletion on renal IRI tolerance and to evaluate its influence in a transplant model of cold ischemia.

Methods: We transplanted renal isografts from C57BL/6 (B6) mice with inducible HDAC2 gene deletion into wild type B6 mice (HDAC2KO->B6), from B6 into inducible HDAC2 deletion mice (B6->HDAC2KO), or B6 into B6 mice (B6->B6). To assess warm IRI tolerance, mice underwent native nephrectomy, tamoxifen-induced HDAC2 deletion, and standardized 25-minute warm IRI with clamping of the transplanted renal pedicle. To evaluate cold IRI tolerance, kidneys were procured from gene-deleted mice, stored on ice for 18 hours before implantation, and transplanted.

Results: HDAC2KO->B6 mice (n =10) demonstrated significant improvement in warm IRI tolerance with lower daily BUN levels over the 4 days following IRI compared to B6->HDAC2KO mice (n=5, p=0.0001) and B6->B6 mice (n=5, p=0.0003) (Figure 1) and significant reduction in renal fibrosis by Sirius Red staining at 28-days post-injury compared to both other groups (p=0.0128 and p=0.0136). HDAC2KO->B6 mice displayed significantly improved BUN (p=0.0187) and Cr (p=0.0012) compared to B6->B6 controls following renal transplant with 18 hours of cold ischemic time and had a trend towards improved survival (80% vs. 67%, p=0.43).

Conclusion: The profound effect of HDAC2 deletion on renal IRI is intrinsic to the kidney and extends to decreased renal injury post-cold ischemia and renal transplantation.

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