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Abstract
Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.
Highlights
Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes
We evaluated the individual roles of three class I HDAC enzymes (HDAC1, 2, and 3) during renal ischemia reperfusion injury (IRI) as part of our ongoing efforts to develop therapies to mitigate functional impairment and renal fibrosis
Renal function was monitored by daily blood urea nitrogen (BUN) and creatinine (Cr) measurements for 4 days post-injury, and kidneys were collected for histologic examination and computerized fibrosis scoring with Sirius Red at 28 days post-op[19]
Summary
Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator. Histone/protein deacetylases (HDAC) enzymes are a highly conserved family of proteins that regulate access of transcriptional machinery to promoter and enhancer sites on coiled chromosomal segments as a result of their regulation of histone acetylation. HDAC1 and 2 have typically been viewed as functionally redundant due to their highly homologous structures[10] Both proteins are located within the nucleus as constituents of nuclear coregulatory complexes (CoREST, NuRD and Sin3), extending their effects on gene expression beyond regulation of histone acetylation 21–24.
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