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Abstract: SA-PO603

Conditional Histone Deacetylase-2 Knockout Within Renal Tubular Cells Is Protective in Renal Ischemia-Reperfusion Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Aufhauser, David Dean, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Concors, Seth, 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
  • Hernandez, Paul T., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Ge, Guanghui, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Hancock, Wayne W., Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Levine, Matthew H., Children's Hospital of Philadelphia and 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. In renal transplantation, IRI contributes to poor outcomes and early graft loss. Histone deacetylases (HDACs) regulate diverse cellular processes. We have previously shown that the class I HDACs 1 and 2 have reciprocal effects on renal ischemia-reperfusion injury (IRI) with HDAC1 deletion increasing vulnerability and HDAC2 protection providing profound protection. A more thorough understanding of the mechanism of this protection, including the site of action, is critical to develop specific targeting in IRI.

Methods

Renal tubule-specific tamoxifen-inducible HDAC-2 knockout (HDAC2-pax8), and tamoxifen-treated WT female (WT) control mice 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-hours post-IRI.

Results

HDAC2-pax8 mice had significant protection from renal injury after renal IRI versus WT mice, as shown by decreased elevations in BUN and Cr post-injury (Figure 1, p<0.005).

Conclusion

Renal tubule-specific HDAC2 deletion is protective in a standardized model of renal warm IRI. We have now moved from showing efficacy with pan-HDAC inhibition to kidney-specific inhibition and now to proximal tubule-specific inhibition. This finding has important translational potential and provides guidance for identifying renal-specific targets for clinical use.

Funding

  • NIDDK Support