Mao Lei, Liu Li, Zhang Tao, Qin Hao, Wu Xiaoyan, Xu Yong
Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.
Department of Geriatric Nephrology, Jiangsu Province Hospital, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Front Cell Dev Biol. 2020 Apr 17;8:235. doi: 10.3389/fcell.2020.00235. eCollection 2020.
Renal fibrosis represents a key pathophysiological process in patients with chronic kidney diseases (CKD) and is typically associated with a poor prognosis. Renal tubular epithelial cells (RTECs), in response to a host of pro-fibrogenic stimuli, can differentiate into myofibroblast-like cells and produce extracellular matrix proteins to promote renal fibrosis. In the present study we investigated the role of histone deacetylase 11 (HDAC11) in this process and the underlying mechanism. We report that expression levels of HDAC11 were up-regulated in the kidneys in several different animal models of renal fibrosis. HDAC11 was also up-regulated by treatment of Angiotensin II (Ang II) in cultured RTECs. Consistently, pharmaceutical inhibition with a small-molecule inhibitor of HDAC11 (quisinostat) attenuated unilateral ureteral obstruction (UUO) induced renal fibrosis in mice. Similarly, HDAC11 inhibition by quisinostat or HDAC11 depletion by siRNA blocked Ang II induced pro-fibrogenic response in cultured RTECs. Mechanistically, HDAC11 interacted with activator protein 2 (AP-2α) to repress the transcription of Kruppel-like factor 15 (KLF15). In accordance, KLF15 knockdown antagonized the effect of HDAC11 inhibition or depletion and enabled Ang II to promote fibrogenesis in RTECs. Therefore, we data unveil a novel AP-2α-HDAC11-KLF15 axis that contributes to renal fibrosis.
肾纤维化是慢性肾脏病（CKD）患者的关键病理生理过程，通常与不良预后相关。肾小管上皮细胞（RTECs）在一系列促纤维化刺激下可分化为肌成纤维细胞样细胞，并产生细胞外基质蛋白以促进肾纤维化。在本研究中，我们调查了组蛋白去乙酰化酶11（HDAC11）在此过程中的作用及其潜在机制。我们报告，在几种不同的肾纤维化动物模型中，肾脏中HDAC11的表达水平上调。在培养的RTECs中，用血管紧张素II（Ang II）处理也可上调HDAC11。同样，用HDAC11的小分子抑制剂（喹西他滨）进行药物抑制可减轻小鼠单侧输尿管梗阻（UUO）诱导的肾纤维化。类似地，喹西他滨抑制HDAC11或siRNA消耗HDAC11可阻断培养的RTECs中Ang II诱导的促纤维化反应。机制上，HDAC11与激活蛋白2（AP-2α）相互作用以抑制Kruppel样因子15（KLF15）的转录。相应地，敲低KLF15可拮抗HDAC11抑制或消耗的作用，并使Ang II能够促进RTECs中的纤维化。因此，我们的数据揭示了一个有助于肾纤维化的新的AP-2α-HDAC11-KLF15轴。
