Ji Yingying, Wang Qi, Wang Jun, Zhang Qi, Jiang Ying, Luan Peipei
Wuxi Central Rehabilitation Hospital, The Affiliated Mental Health Center of Jiangnan University, Wuxi 213151, Jiangsu, China.
Int J Endocrinol. 2025 Jul 16;2025:1186113. doi: 10.1155/ije/1186113. eCollection 2025.
Diabetic nephropathy, a leading cause of end-stage renal disease, is a major health concern. Its early-stage signs are unclear. Endothelial dysfunction, an early indicator, is suitable for early detection and intervention. However, current treatments mainly focus on glycemic and blood pressure control, lacking specific methods for targeting this dysfunction. We reanalyzed GSE13535 dataset, which has single-cell RNA-seq of high-glucose-exposed endothelial cells. HUVECs were cultured in high-glucose and TNF-α. We conducted RNA extraction, qPCR, western blotting, iron measurement, TUNEL assay, and bioinformatics analysis. An antiferroptosis drug was used in STZ-treated diabetic mice. Single-cell RNA-seq showed early endothelial cell dysfunction, along with ENDMT, cytokine release, and ferroptosis activation. SLC3A2 was identified as a key; its reduced expression was linked to more inflammation, fibrosis, and ferroptosis. Diabetic mice had low SLC3A2 and more ferroptosis in glomerular endothelial cells. A STAT1 inhibitor alleviated endothelial dysfunction. Endothelial dysfunction and ferroptosis are crucial in diabetic nephropathy. Identifying SLC3A2 as a key regulator gives insights into potential treatments. Fludarabine shows promise. Further research on mechanisms and strategies is needed to improve patient outcomes.
糖尿病肾病是终末期肾病的主要病因，是一个重大的健康问题。其早期症状尚不明确。内皮功能障碍作为早期指标，适用于早期检测和干预。然而，目前的治疗主要集中在血糖和血压控制上，缺乏针对这种功能障碍的具体方法。我们重新分析了GSE13535数据集，该数据集包含高糖暴露内皮细胞的单细胞RNA测序数据。人脐静脉内皮细胞（HUVECs）在高糖和肿瘤坏死因子-α（TNF-α）环境中培养。我们进行了RNA提取、定量聚合酶链反应（qPCR）、蛋白质免疫印迹法、铁含量测定、末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）检测和生物信息学分析。一种抗铁死亡药物被用于链脲佐菌素（STZ）处理的糖尿病小鼠。单细胞RNA测序显示早期内皮细胞功能障碍，伴有内皮-间充质转化（ENDMT）、细胞因子释放和铁死亡激活。溶质载体家族3成员2（SLC3A2）被确定为关键因素；其表达降低与更多炎症、纤维化和铁死亡有关。糖尿病小鼠肾小球内皮细胞中SLC3A2水平较低且铁死亡更多。一种信号转导和转录激活因子1（STAT1）抑制剂减轻了内皮功能障碍。内皮功能障碍和铁死亡在糖尿病肾病中至关重要。将SLC3A2确定为关键调节因子为潜在治疗提供了思路。氟达拉滨显示出前景。需要进一步研究机制和策略以改善患者预后。
