Yu Dehai, Luo Ling, Liang Yu, Zhou Huili, Xiao Yinghui, An Xingna, Wang Yingzhao, Xu Zhonggao, Sun Weixia, Wang Wanning
Department of Core Facility, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China.
Front Endocrinol (Lausanne). 2025 Jun 9;16:1426854. doi: 10.3389/fendo.2025.1426854. eCollection 2025.
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.
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 β-Gal staining. Western blotting was performed to analyze ER-α36 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-α36 on EZH2 and PTEN were examined, and chromatin immunoprecipitation (ChIP) was used to assess H3K27me3 modifications at the PTEN promoter.
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-α36 overexpression partially restored PI3K/AKT signaling, attenuated cellular injury, and reversed HG-induced epigenetic changes at the PTEN locus.
Our findings demonstrate that ER-α36 protects renal tubular cells from HG-induced damage through EZH2-mediated epigenetic regulation of PTEN and PI3K/AKT pathway activation. These results identify ER-α36 as a potential therapeutic target for DKD.
雌激素 - 雌激素受体（ER）系统在糖尿病肾病（DKD）的性别差异中起重要作用，但其在糖尿病条件下对肾小管损伤的具体影响仍未完全明确。
将人肾小管（HK - 2）细胞暴露于高糖（HG）环境以模拟糖尿病条件。通过流式细胞术定量细胞凋亡，通过β - 半乳糖苷酶染色评估细胞衰老。进行蛋白质印迹分析以检测ER - α36表达、PI3K/AKT通路活性、凋亡调节因子（Bcl - 2、Bax、裂解的caspase - 3/7）和衰老标志物（P53、P21、P27、P16）。研究了ER - α36对EZH2和PTEN的调节作用，并使用染色质免疫沉淀（ChIP）评估PTEN启动子处的H3K27me3修饰。
HG处理显著诱导HK - 2细胞凋亡和衰老，同时抑制PI3K/AKT信号传导。这些效应与EZH2表达下调和PTEN启动子处H3K27me3富集减少有关，导致PTEN上调。ER - α36过表达部分恢复了PI3K/AKT信号传导，减轻了细胞损伤，并逆转了HG诱导的PTEN基因座表观遗传变化。
我们的研究结果表明，ER - α36通过EZH2介导的PTEN表观遗传调控和PI3K/AKT通路激活保护肾小管细胞免受HG诱导的损伤。这些结果确定ER - α36为DKD的潜在治疗靶点。
