Zhang Yingying, Yu Chen, Agborbesong Ewud, Li Xiaogang
Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Department of Nephrology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
FASEB J. 2025 May 15;39(9):e70605. doi: 10.1096/fj.202500128R.
Renal epithelial cell senescence and kidney aging have become the focus of scientific investigation. However, how epigenetic regulation in these processes remains elusive. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, regulates trimethylation of histone H3 at lysine 27 (H3K27me3) and plays an important role in renal pathophysiology. In this study, we show that the expression of EZH2 is decreased in naturally aged and irradiation (IR)-induced mouse kidneys, as well as in IR-induced human renal cortical tubular epithelial (RCTE) cells through proteasome-mediated degradation. Inhibition of EZH2 with its specific inhibitor 3-DZNeP promotes tubular cell senescence and kidney aging characterized by an increase in the expression of senescence markers, including p16 and p21, in mouse kidneys and in IR-induced RCTE cells. We show that EZH2 represses the transcription of p16 through trimethylation of H3K27me3, which directly binds to the promoter of p16. EZH2 represses the transcription of p21 through directly binding to the promoter of p21, and this process is involved in its interaction with p53 and its phosphorylation by ataxia-telangiectasia mutated (ATM), a critical protein involved in the cellular response to DNA damage. Inhibition of ATM with its inhibitor decreased the phosphorylation of EZH2 and the binding of EZH2 to the promoter of p21 in IR-treated RCTE cells in a p53-dependent manner. This study suggests that EZH2 plays a critical role in preventing kidney aging and DNA-damage-induced renal tubular cellular senescence, in which senescence and kidney aging also result in the destabilization of EZH2, forming a negative feedback loop.
肾上皮细胞衰老和肾脏老化已成为科学研究的焦点。然而，这些过程中的表观遗传调控机制仍不清楚。zeste同源物2增强子（EZH2）是一种组蛋白甲基转移酶，可调节组蛋白H3赖氨酸27位点的三甲基化（H3K27me3），并在肾脏病理生理学中发挥重要作用。在本研究中，我们发现EZH2的表达在自然衰老和辐射（IR）诱导的小鼠肾脏中以及在IR诱导的人肾皮质肾小管上皮（RCTE）细胞中通过蛋白酶体介导的降解而降低。用其特异性抑制剂3-DZNeP抑制EZH2可促进肾小管细胞衰老和肾脏老化，其特征是小鼠肾脏和IR诱导的RCTE细胞中衰老标志物（包括p16和p21）的表达增加。我们发现EZH2通过H3K27me3的三甲基化抑制p16的转录，而H3K27me3直接结合到p16的启动子上。EZH2通过直接结合p21的启动子来抑制p21的转录，并且该过程涉及其与p53的相互作用以及由共济失调毛细血管扩张突变（ATM）介导的磷酸化，ATM是一种参与细胞对DNA损伤反应的关键蛋白。用其抑制剂抑制ATM以p53依赖的方式降低了IR处理的RCTE细胞中EZH2的磷酸化以及EZH2与p21启动子的结合。本研究表明，EZH2在预防肾脏老化和DNA损伤诱导的肾小管细胞衰老中起关键作用，其中衰老和肾脏老化也导致EZH2的不稳定，形成负反馈环。
