Wan Jiao, Hou Xiaoyan, Zhou Zhanmei, Geng Jian, Tian Jianwei, Bai Xiaoyan, Nie Jing
Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangzhou, Guangdong, PR China.
Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, PR China.
Free Radic Biol Med. 2017 Jul;108:280-299. doi: 10.1016/j.freeradbiomed.2017.03.012. Epub 2017 Mar 16.
Epigenetic modulation of podocyte injury plays a pivotal role in diabetic nephropathy (DN). Wilm's tumor 1 (WT1) has been found to have opposing roles with β-catenin in podocyte biology. Herein, we asked whether the histone methyltransferase enzyme enhancer of zeste homolog 2 (EZH2) promotes WT1-induced podocyte injury via β-catenin activation and the underlying mechanisms. We found that WT1 antagonized EZH2 and ameliorated β-catenin-mediated podocyte injury as demonstrated by attenuated podocyte mesenchymal transition, maintenance of podocyte architectural integrity, decreased podocyte apoptosis and oxidative stress. Further, we provided mechanistical evidence that EZH2 was required in WT1-mediated β-catenin inactivation via repression of secreted frizzled-related protein 1 (SFRP-1), a Wnt antagonist. Moreover, EZH2-mediated silencing of SFRP-1 was due to increased histone 3 lysine 27 trimethylation (H3K27me3) on its promoter region. WT1 favored renal function and decreased podocyte injury in diabetic rats and DN patients. Notably, WT1 exhibited clinical and biological relevance as it was linked to dropped serum creatinine, decreased proteinuria and elevated estimated glomerular filtration rate (eGFR). We propose an epigenetic process via the WT1/EZH2/β-catenin axis in attenuating podocyte injury in DN. Targeting WT1 and EZH2 could be potential therapeutic approaches for DN.
足细胞损伤的表观遗传调控在糖尿病肾病（DN）中起关键作用。已发现威尔姆斯瘤1（WT1）在足细胞生物学中与β-连环蛋白具有相反的作用。在此，我们探讨组蛋白甲基转移酶zeste同源物2增强子（EZH2）是否通过激活β-连环蛋白促进WT1诱导的足细胞损伤及其潜在机制。我们发现WT1拮抗EZH2并改善β-连环蛋白介导的足细胞损伤，表现为足细胞间充质转化减弱、足细胞结构完整性维持、足细胞凋亡和氧化应激减少。此外，我们提供了机制证据，表明EZH2通过抑制分泌型卷曲相关蛋白1（SFRP-1，一种Wnt拮抗剂）参与WT1介导的β-连环蛋白失活。而且，EZH2介导的SFRP-1沉默是由于其启动子区域组蛋白3赖氨酸27三甲基化（H3K27me3）增加。WT1有利于糖尿病大鼠和DN患者的肾功能并减少足细胞损伤。值得注意的是，WT1具有临床和生物学相关性，因为它与血清肌酐下降、蛋白尿减少和估计肾小球滤过率（eGFR）升高有关。我们提出了一个通过WT1/EZH2/β-连环蛋白轴减轻DN中足细胞损伤的表观遗传过程。靶向WT1和EZH2可能是DN的潜在治疗方法。
