ER-α36 prevents high glucose-induced cellular senescence and apoptosis in renal tubular cell.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.