Department of Surgery, University of Wisconsin, Madison, WI, USA.
Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
Sci Rep. 2021 Apr 27;11(1):9018. doi: 10.1038/s41598-021-88242-3.
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.
组蛋白/蛋白质去乙酰化酶（HDAC）1 和 2 通常被视为存在于各种共调节复合物中的结构和功能相似的酶。我们使用诱导型敲除小鼠测试了这些同工酶在肾缺血再灌注损伤（IRI）中的差异效应，发现 HDAC1 缺失对缺血耐受性没有显著影响，但 HDAC2 缺失可减轻缺血性损伤。通过移植或 PAX8 控制的近端肾小管特异性 Cre 将 HDAC2 缺失限制在肾脏中，可导致肾 IRI 保护。HDAC2 的药理抑制增加了肾脏中的组蛋白乙酰化，但并未延长肾脏保护作用。蛋白质分析表明，与 WT 细胞相比，HDAC2-/-细胞中 HDAC1 相关的 CoREST 蛋白增加，这表明在没有 HDAC2 的情况下，CoREST 复合物对 HDAC1 的占据增加可稳定该复合物。体内给予 CoREST 抑制剂可加重 WT 小鼠的肾脏损伤，并消除 HDAC2 缺失的益处。内皮素的基因表达分析显示，HDAC2 缺失时内皮素水平降低。这些数据表明，HDAC1 和 2 对肾小管中 CoREST 复合物稳定性的相反影响可能会影响肾 IRI 的结果，并暗示内皮素作为一种潜在的下游介质。
