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

Dehai Yu¹Ling Luo¹Yu Liang²Yinghui Xiao¹Xingna An¹Yingzhao Wang³Kejian Gong⁴Zhonggao Xu⁵Weixia Sun^5*Wanning Wang^5*

• ¹Core Facility, First Affiliated Hospital of Jilin University, Changchun, China
• ²Nephrology Department, First Affiliated Hospital of Jilin University, Changchun, China
• ³Department of Neurology, Jilin Qianwei Hospital, Changchun, Jilin Province, China
• ⁴Department of Thoracic Surgery, First Affiliated Hospital of Jilin University, Changchun, China
• ⁵Department of Nephrology, First Affiliated Hospital of Jilin University, Changchun, China

Studies have shown a correlation between gender and the prevalence and progression of diabetic kidney disease (DKD), with the estrogen-estrogen receptor (ER) system believed to play a significant role in the sexual dimorphism of DKD. However, the impact of the estrogen-ER system on renal tubular cell behavior in DKD remains unclear. In this study, we investigated the effects of high glucose (HG) on human renal tubular cells (HK-2) and the expression of ER-α36, a variant of ER-α66. We also examined the molecular mechanisms by which ER-α36 regulates HK-2 cell behavior under HG conditions. Our results revealed that HG significantly induced apoptosis and senescence in HK-2 cells, accompanied by activation (or suppression) of apoptosisrelated proteins (Bcl-2/Bax/Casp3/Casp7) and senescence-related proteins (P53/P21/P27/P16). Furthermore, we found that HG induced apoptosis and senescence in HK-2 cells by inhibiting the PI3K/AKT signaling pathway, while overexpression of ER-α36 in HK-2 cells partially activated the PI3K/AKT pathway and attenuated HGinduced cell apoptosis and senescence. Additionally, we found that HG can downregulate the expression of enhancer of zeste homolog 2 (EZH2) and suppress H3K27me3 level, thereby promoting PTEN transcription. Overexpression of ER-α36 reversed this process. ChIP experiments also showed that HG inhibited histone methylation on the PTEN promoter, while overexpression of ER-α36 reversed the methylation levels at these sites. In summary, in this study, we found that under HG conditions, ER-α36 can influence PTEN promoter histone methylation and PI3K/AKT phosphorylation by regulating EZH2, ultimately affecting HG-induced cell apoptosis and senescence. Our findings provide a new insight into the treatment of DKD.