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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)\u2010induced mouse kidneys, as well as in IR\u2010induced human renal cortical tubular epithelial (RCTE) cells through proteasome\u2010mediated degradation. Inhibition of EZH2 with its specific inhibitor 3\u2010DZNeP 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\u2010induced 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\u2010telangiectasia 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\u2010treated RCTE cells in a p53\u2010dependent manner. This study suggests that EZH2 plays a critical role in preventing kidney aging and DNA\u2010damage\u2010induced renal tubular cellular senescence, in which senescence and kidney aging also result in the destabilization of EZH2, forming a negative feedback loop.<\/jats:p>","DOI":"10.1096\/fj.202500128r","type":"journal-article","created":{"date-parts":[[2025,5,6]],"date-time":"2025-05-06T08:59:43Z","timestamp":1746521983000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Downregulation of\n                    <scp>EZH2<\/scp>\n                    Promotes Renal Epithelial Cellular Senescence and Kidney Aging"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-5866","authenticated-orcid":false,"given":"Yingying","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Nephrology, Shanghai Tongji Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7169-276X","authenticated-orcid":false,"given":"Chen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Shanghai Tongji Hospital Tongji University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewud","family":"Agborbesong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Biochemistry and Molecular Biology Mayo Clinic  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Mayo Clinic  Rochester Minnesota USA"},{"name":"Department of Biochemistry and Molecular Biology Mayo Clinic  Rochester Minnesota 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