Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.
Class I HDAC activity is required for renal protection and regeneration after acute kidney injury.
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DOI：
10.1152/ajprenal.00102.2014
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发表时间：
2014-08
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影响因子：
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通讯作者：
Jinhua Tang;Yanli Yan;T. Zhao;R. Gong;G. Bayliss;Haidong Yan;S. Zhuang
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作者：
Jinhua Tang;Yanli Yan;T. Zhao;R. Gong;G. Bayliss;Haidong Yan;S. Zhuang
组蛋白去乙酰化酶（HDAC）的激活是肾上皮细胞增殖和肾脏发育所必需的。然而，它们在急性肾损伤（阿基）后肾小管细胞存活和再生中的作用仍不清楚。在这项研究中，我们证明了所有I类HDAC亚型（1，2，3和8）在小鼠肾脏的肾上皮细胞中表达。在叶酸或横纹肌溶解诱导的阿基小鼠模型中，使用MS-275（一种高选择性抑制剂）抑制I类HDAC导致更严重的肾小管损伤，如肾功能不全恶化、中性粒细胞明胶酶相关脂质运载蛋白表达增加以及细胞凋亡和半胱天冬酶-3活化增强所示。阻断I类HDAC活性也损害肾再生，如肾Pax-2、波形蛋白和增殖细胞核抗原表达降低所证明。肾脏损伤伴随着表皮生长因子受体（EGFR）、信号转导和转录激活因子3（STAT 3）和Akt的磷酸化增加。抑制I类HDAC抑制EGFR磷酸化以及减少其表达。MS-275也有效抑制STAT 3和Akt磷酸化，但这种处理不影响其表达水平。总之，这些数据表明I类HDAC活性有助于肾保护和功能恢复，并且是阿基后肾再生所需的。此外，肾EGFR信号传导受到这类HDAC的调节。
Activation of histone deacetylases (HDACs) is required for renal epithelial cell proliferation and kidney development. However, their role in renal tubular cell survival and regeneration after acute kidney injury (AKI) remains unclear. In this study, we demonstrated that all class I HDAC isoforms (1, 2, 3, and 8) were expressed in the renal epithelial cells of the mouse kidney. Inhibition of class I HDACs with MS-275, a highly selective inhibitor, resulted in more severe tubular injury in the mouse model of AKI induced by folic acid or rhabdomyolysis, as indicated by worsening renal dysfunction, increased neutrophil gelatinase-associated lipocalin expression, and enhanced apoptosis and caspase-3 activation. Blocking class I HDAC activity also impaired renal regeneration as evidenced by decreased expression of renal Pax-2, vimentin, and proliferating cell nuclear antigen. Injury to the kidney is accompanied by increased phosphorylation of epidermal growth factor receptor (EGFR), signal transducers and activators of transcription 3 (STAT3), and Akt. Inhibition of class I HDACs suppressed EGFR phosphorylation as well as reduced its expression. MS-275 was also effective in inhibiting STAT3 and Akt phosphorylation, but this treatment did not affect their expression levels. Taken together, these data suggest that the class I HDAC activity contributes to renal protection and functional recovery and is required for renal regeneration after AKI. Furthermore, renal EGFR signaling is subject to regulation by this class of HDACs.