Abstract: TH-PO228

HDAC2 Deletion Mitigates Renal Ischemia-Reperfusion Injury by Stabilizing the CoREST Complex

Session Information

Category: Acute Kidney Injury

  • 001 AKI: Basic

Authors

  • Aufhauser, David Dean, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Murken, Douglas R., University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Wang, Zhonglin, University of Pennvania, Philadelphia, Pennsylvania, United States
  • Ge, Guanghui, University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Concors, Seth, University of Pennsylvania Health System, Philadelphia, Pennsylvania, United States
  • Bhatti, Tricia, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Hancock, Wayne W., Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
  • Levine, Matthew H., University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

Class I histone/protein deacetylases (HDAC) 1 and 2 have reciprocal effects on renal ischemia-reperfusion injury (IRI) with HDAC1 deletion increasing vulnerability and HDAC2 protection providing profound protection. HDAC1 and 2 typically interact as heterodimers in multimeric corepressor complexes and are conventionally been viewed as functionally redundant.

Methods

Wild type C57BL/6 (WT) and whole animal-inducible HDAC1- or 2- gene deleted mice (HDAC1-/- or HDAC2-/-) were used in this study. Primary renal tubular epithelial cell (RTEC) cultures were derived from each genetic strain for protein analysis via Western blot. Standardized warm renal IRI was achieved through unilateral clamping of the renal pedicle and contralateral nephrectomy.

Results

In nuclear extracts, HDAC1 and 2 deficient RTEC have compensatory enhanced protein expression of the other (Fig 1a). HDAC1 pulldown in HDAC2 deficient RTEC demonstrated enhanced association with CoREST and LSD1 compared to wild type RTEC (Fig 1b). HDAC2 pulldowns in HDAC1 deficient RTECs showed no enhanced association with CoREST. In vivo CoREST inhibition increased vulnerability to renal IRI injury in both WT and HDAC2-/- mice and returned HDAC2-/- mice to a WT renal IRI phenotype (Fig 1c).

Conclusion

HDAC2 deletion leads to increased associated between HDAC1 and other members of the CoREST complex, indicating increased complex stability. Inhibition of the CoREST complex in vivo reverses the protection seen with HDAC2 deletion.

Funding

  • NIDDK Support