Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Medicine, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island; and.
Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Emergency Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China;
Am J Physiol Renal Physiol. 2014 Aug 1;307(3):F303-16. doi: 10.1152/ajprenal.00102.2014. Epub 2014 May 7.
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.
组蛋白去乙酰化酶（HDACs）的激活对于肾上皮细胞增殖和肾脏发育是必需的。然而，它们在急性肾损伤（AKI）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 同工型（1、2、3 和 8）在小鼠肾脏的肾上皮细胞中表达。用高度选择性抑制剂 MS-275 抑制 I 类 HDACs 会导致叶酸或横纹肌溶解诱导的 AKI 小鼠模型中更严重的肾小管损伤，表现为肾功能恶化、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 激活增强。阻断 I 类 HDAC 活性也会损害肾脏再生，表现为肾脏 Pax-2、波形蛋白和增殖细胞核抗原表达减少。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（STAT3）和 Akt 的磷酸化增加。抑制 I 类 HDAC 会抑制 EGFR 磷酸化并降低其表达。MS-275 还能有效抑制 STAT3 和 Akt 的磷酸化，但这种治疗方法并不影响它们的表达水平。总之，这些数据表明 I 类 HDAC 活性有助于肾脏保护和功能恢复，并在 AKI 后促进肾脏再生。此外，肾 EGFR 信号受到该类 HDACs 的调节。
