Diabetic retinopathy (DR) is the most common ocular fundus disease in diabetic patients. Chronic hyperglycemia not only promotes the development of diabetes and its complications, but also aggravates the occurrence of senescence. Previous studies have shown that DR is associated with senescence, but the specific mechanism has not been fully elucidated. Here, we first detected the differentially expressed genes (DEGs) and cellular senescence level of db/db mouse retinas by bulk RNA sequencing. Then, we used single-cell sequencing (scRNA-seq) to identify the main cell types in the retina and analyzed the DEGs in each cluster. We demonstrated that p53 expression was significantly increased in retinal endothelial cell cluster of db/db mice. Inhibition of p53 can reduce the expression of SA-β-Gal and the senescence-associated secretory phenotype (SASP) in HRMECs. Finally, we found that p53 can promote FoxO3a ubiquitination and degradation by increasing the expression of the ubiquitin-conjugating enzyme UBE2L6. Overall, our results demonstrate that p53 can accelerate the senescence process of endothelial cells and aggravate the development of DR. These data reveal new targets and insights that may be used to treat DR.

中文翻译：

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p53 通过 UBE2L6 增强 FoxO3a 泛素化和降解，加速糖尿病视网膜病变中的内皮细胞衰老

糖尿病视网膜病变（DR）是糖尿病患者最常见的眼底疾病。慢性高血糖不仅促进糖尿病及其并发症的发生，而且还会加剧衰老的发生。既往研究表明DR与衰老相关，但具体机制尚未完全阐明。在这里，我们首先通过批量RNA测序检测了db/db小鼠视网膜的差异表达基因（DEG）和细胞衰老水平。然后，我们使用单细胞测序（scRNA-seq）来识别视网膜中的主要细胞类型，并分析每个簇中的DEG。我们证明 p53 表达在 db/db 小鼠的视网膜内皮细胞簇中显着增加。抑制 p53 可以减少 HRMEC 中 SA-β-Gal 的表达和衰老相关的分泌表型 (SASP)。最后，我们发现p53可以通过增加泛素结合酶UBE2L6的表达来促进FoxO3a泛素化和降解。总的来说，我们的结果表明p53可以加速内皮细胞的衰老过程并加剧DR的发展。这些数据揭示了可用于治疗 DR 的新目标和见解。