Bin Huang, Wen Wenjie
Department of Endocrinology, Division of Life Science and Medicine, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei, 230000, China.
Anhui Province Engineering Research Center for Dental Materials and Application, School of Stomatology, Wannan Medical College, Wuhu, 241002, China.
Int Urol Nephrol. 2025 May 9. doi: 10.1007/s11255-025-04562-7.
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes that can lead to end-stage renal failure. Emerging evidence suggests that endoplasmic reticulum (ER) stress plays a crucial role in the pathogenesis of DKD by affecting various renal parenchymal cells, including endothelial cells, podocytes, and mesangial cells. This review comprehensively examines the relationship between ER stress and DKD, focusing on how metformin, a first-line antidiabetic medication, ameliorates ER stress-induced kidney injury. Multiple factors, including reactive oxygen species (ROS), proteinuria, and advanced glycation end products (AGEs), contribute to ER stress in DKD. Metformin's renoprotective effects are primarily mediated through activation of the AMPK signaling pathway, which modulates ER stress response, reduction of oxidative stress and its impact on ER function, and improvement of mitochondrial function. These mechanisms collectively lead to decreased proteinuria, reduced cell apoptosis, and attenuated epithelial-mesenchymal transition in diabetic kidneys. Understanding these molecular mechanisms provides new insights into the therapeutic potential of metformin in DKD treatment. However, further research is needed to elucidate the precise molecular pathways through which metformin regulates ER stress in different renal cell types under diabetic conditions.
糖尿病肾病（DKD）是糖尿病常见的微血管并发症，可导致终末期肾衰竭。新出现的证据表明，内质网（ER）应激通过影响各种肾实质细胞，包括内皮细胞、足细胞和系膜细胞，在DKD的发病机制中起关键作用。本综述全面探讨了ER应激与DKD之间的关系，重点关注一线抗糖尿病药物二甲双胍如何改善ER应激诱导的肾损伤。多种因素，包括活性氧（ROS）、蛋白尿和晚期糖基化终末产物（AGEs），促成了DKD中的ER应激。二甲双胍的肾脏保护作用主要通过激活AMPK信号通路介导，该通路调节ER应激反应、降低氧化应激及其对ER功能的影响，并改善线粒体功能。这些机制共同导致糖尿病肾脏中蛋白尿减少、细胞凋亡减少以及上皮-间质转化减弱。了解这些分子机制为二甲双胍在DKD治疗中的治疗潜力提供了新的见解。然而，需要进一步研究以阐明在糖尿病条件下二甲双胍调节不同肾细胞类型中ER应激的精确分子途径。
