Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis
Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis
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zeste 同源物 2 增强子的遗传或药理学阻断可抑制腹膜纤维化的进展
DOI：
10.1002/path.5352
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发表时间：
2019-11-14
影响因子：
7.3
通讯作者：
Liu, Na
中科院分区：
文献类型：
--
作者：
Shi, Yingfeng;Tao, Min;Liu, Na
组蛋白甲基转移酶增强子zeste同源物2（EZH 2）的失调已经涉及许多癌症的发病机制。然而，EZH 2在腹膜纤维化中的作用仍然未知。我们研究了EZH 2在腹膜透析（PD）患者中的表达，并通过使用3-去氮普兰霉素A（3-DZNeP）和EZH 2条件性敲除小鼠，评估了其在培养的人腹膜间皮细胞（HPMCs）和由葡萄糖酸氯己定（CG）或高糖腹膜透析液（PDF）诱导的腹膜纤维化小鼠模型中的腹膜纤维化中的作用。在PD相关性腹膜炎患者的腹膜和长期PD患者的透析流出物中检测到丰富的EZH 2，其与TGF-β1、血管内皮生长因子和IL-6的表达呈正相关。EZH 2在CG或PDF损伤后的小鼠腹膜中高度表达。在两种小鼠模型中，3-DZNeP治疗减轻了腹膜纤维化，并抑制了几种促纤维化信号通路的激活，包括TGF-β1/Smad 3、Notch 1、表皮生长因子受体和Src。EZH 2抑制还抑制STAT 3和核因子-κB磷酸化，并减少淋巴细胞和巨噬细胞浸润和损伤腹膜中的血管生成。3-DZNeP通过降低血液尿素氮的透析液-血浆比和增加PDF注射后2 h透析液葡萄糖与初始透析液葡萄糖的比值，有效改善了高糖PDF相关的腹膜功能障碍。此外，延迟给予3-DZNeP可抑制腹膜纤维化进展，逆转已建立的腹膜纤维化，并降低金属蛋白酶2和基质金属蛋白酶-2和-9的组织抑制剂的表达。最后，EZH 2-KO小鼠表现出比EZH 2-WT小鼠更少的腹膜纤维化。在HPMC中，用EZH 2 siRNA或3-DZNeP处理抑制了TGF-β1诱导的α-SMA和胶原I的上调，并保留了E-钙粘蛋白。这些结果表明EZH 2是促进腹膜纤维化的关键表观遗传调节因子。靶向EZH 2可能具有预防和治疗腹膜纤维化的潜力。© 2019大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in peritoneal fibrosis remains unknown. We investigated EZH2 expression in peritoneal dialysis (PD) patients and assessed its role in peritoneal fibrosis in cultured human peritoneal mesothelial cells (HPMCs) and murine models of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or high glucose peritoneal dialysis fluid (PDF) by using 3‐deazaneplanocin A (3‐DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long‐term PD patients, which was positively correlated with expression of TGF‐β1, vascular endothelial growth factor, and IL‐6. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3‐DZNeP attenuated peritoneal fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF‐β1/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor‐κB phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3‐DZNeP effectively improved high glucose PDF‐associated peritoneal dysfunction by decreasing the dialysate‐to‐plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2 h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3‐DZNeP inhibited peritoneal fibrosis progression, reversed established peritoneal fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase‐2 and ‐9. Finally, EZH2‐KO mice exhibited less peritoneal fibrosis than EZH2‐WT mice. In HPMCs, treatment with EZH2 siRNA or 3‐DZNeP suppressed TGF‐β1‐induced upregulation of α‐SMA and Collagen I and preserved E‐cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes peritoneal fibrosis. Targeting EZH2 may have the potential to prevent and treat peritoneal fibrosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.