Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, PR China.
Department of Nephrology, Shanghai Songjiang District Central Hospital, Shanghai, PR China.
J Pathol. 2020 Jan;250(1):79-94. doi: 10.1002/path.5352. Epub 2019 Nov 14.
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.
组蛋白甲基转移酶增强子的锌指蛋白 2（EZH2）的失调与许多癌症的发病机制有关。然而，EZH2 在腹膜纤维化中的作用尚不清楚。我们研究了接受腹膜透析（PD）治疗的患者中 EZH2 的表达，并通过使用 3-去氮杂胞苷（3-DZNeP）和 EZH2 条件性敲除小鼠，在体外培养的人腹膜间皮细胞（HPMCs）和氯化十六烷基吡啶（CG）或高糖腹膜透析液（PDF）诱导的腹膜纤维化的小鼠模型中评估了其在腹膜纤维化中的作用。在 PD 相关腹膜炎患者的腹膜和长期 PD 患者的透析液中检测到大量 EZH2，其与 TGF-β1、血管内皮生长因子和 IL-6 的表达呈正相关。在 CG 或 PDF 损伤后，EZH2 在小鼠的腹膜中高表达。在这两种小鼠模型中，用 3-DZNeP 治疗可减轻腹膜纤维化并抑制几条促纤维化信号通路的激活，包括 TGF-β1/Smad3、Notch1、表皮生长因子受体和 Src。EZH2 抑制还抑制了 STAT3 和核因子-κB 的磷酸化，并减少了损伤腹膜中的淋巴细胞和巨噬细胞浸润和血管生成。3-DZNeP 通过降低血液尿素氮的透析液与血浆比，并增加 PDF 注射后 2 小时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 可抑制腹膜纤维化的进展，逆转已建立的腹膜纤维化，并降低组织金属蛋白酶抑制剂 2、基质金属蛋白酶-2 和 -9 的表达。最后，EZH2-KO 小鼠的腹膜纤维化程度低于 EZH2-WT 小鼠。在 HPMCs 中，用 EZH2 siRNA 或 3-DZNeP 治疗可抑制 TGF-β1 诱导的 α-SMA 和 Collagen I 的上调，并保持 E-钙粘蛋白。这些结果表明，EZH2 是一种促进腹膜纤维化的关键表观遗传调节剂。靶向 EZH2 可能具有预防和治疗腹膜纤维化的潜力。
