Department of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; Department of Nephrology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
J Biol Chem. 2024 Sep;300(9):107598. doi: 10.1016/j.jbc.2024.107598. Epub 2024 Jul 24.
In recent years, a surge in studies investigating N6-methyladenosine (mA) modification in human diseases has occurred. However, the specific roles and mechanisms of mA in kidney disease remain incompletely understood. This study revealed that mA plays a positive role in regulating renal fibrosis (RF) by inducing epithelial-to-mesenchymal phenotypic transition (EMT) in renal tubular cells. Through comprehensive analyses, including mA sequencing, RNA-seq, and functional studies, we confirmed the pivotal involvement of zinc finger E-box binding homeobox 2 (ZEB2) in mA-mediated RF and EMT. Notably, the mA-modified coding sequence of ZEB2 mRNA significantly enhances its translational elongation and mRNA stability by interacting with the YTHDF1/eEF-2 complex and IGF2BP3, respectively. Moreover, targeted demethylation of ZEB2 mRNA using the dmACRISPR system substantially decreases ZEB2 expression and disrupts the EMT process in renal tubular epithelial cells. In vivo and clinical data further support the positive influence of mA/ZEB2 on RF progression. Our findings highlight the mA-mediated regulation of RF through ZEB2, revealing a novel therapeutic target for RF treatment and enhancing our understanding of the impact of mRNA methylation on kidney disease.
近年来，研究 N6-甲基腺苷（m6A）修饰在人类疾病中的作用的研究呈爆炸式增长。然而，m6A 在肾脏疾病中的具体作用和机制仍不完全清楚。本研究揭示 m6A 通过诱导肾小管细胞上皮-间充质转化（EMT），在调节肾纤维化（RF）中发挥积极作用。通过 m6A 测序、RNA-seq 和功能研究等综合分析，我们证实锌指 E 盒结合同源盒 2（ZEB2）在 m6A 介导的 RF 和 EMT 中起关键作用。值得注意的是，m6A 修饰的 ZEB2 mRNA 编码序列通过与 YTHDF1/eEF-2 复合物和 IGF2BP3 相互作用，分别显著增强其翻译延伸和 mRNA 稳定性。此外，使用 dmACRISPR 系统靶向去甲基化 ZEB2 mRNA 可显著降低肾小管上皮细胞中 ZEB2 的表达并破坏 EMT 过程。体内和临床数据进一步支持 m6A/ZEB2 对 RF 进展的积极影响。我们的研究结果强调了 m6A 通过 ZEB2 调节 RF，揭示了 RF 治疗的新治疗靶点，并加深了我们对 mRNA 甲基化对肾脏疾病影响的理解。
