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Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The estrogen-estrogen receptor (ER) system plays a significant role in the sexual dimorphism of diabetic kidney disease (DKD), yet its specific effects on renal tubular injury under diabetic conditions remain incompletely characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Human renal tubular (HK-2) cells were exposed to high glucose (HG) to model diabetic conditions. Cell apoptosis was quantified by flow cytometry, and cell senescence was assessed via \u03b2-Gal staining. Western blotting was performed to analyze ER-\u03b136 expression, PI3K\/AKT pathway activity, apoptosis regulators (Bcl-2, Bax, cleaved caspase-3\/7), and senescence markers (P53, P21, P27, P16). The regulatory effects of ER-\u03b136 on EZH2 and PTEN were examined, and chromatin immunoprecipitation (ChIP) was used to assess H3K27me3 modifications at the PTEN promoter.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>HG treatment significantly induced apoptosis and senescence in HK-2 cells, concomitant with the suppression of PI3K\/AKT signaling. These effects were associated with the downregulated EZH2 expression and reduced H3K27me3 enrichment at the PTEN promoter, leading to PTEN upregulation. ER-\u03b136 overexpression partially restored PI3K\/AKT signaling, attenuated cellular injury, and reversed HG-induced epigenetic changes at the PTEN locus.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings demonstrate that ER-\u03b136 protects renal tubular cells from HG-induced damage through EZH2-mediated epigenetic regulation of PTEN and PI3K\/AKT pathway activation. These results identify ER-\u03b136 as a potential therapeutic target for DKD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2025.1426854","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T04:11:03Z","timestamp":1749442263000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["ER-\u03b136 prevents high glucose-induced cellular senescence and apoptosis in renal tubular 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