Yan Zijie, Xu Jinghan, Liu Tianjiao, Wang Li, Zhang Qi, Li Xiaoling, Lin Bingjing, Piao Chunli
Endocrinology Department, Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People's Republic of China.
Diabetes Metab Syndr Obes. 2025 Sep 8;18:3323-3341. doi: 10.2147/DMSO.S543814. eCollection 2025.
Diabetic Kidney Disease (DKD), one of the most severe microvascular complications of diabetes, significantly elevates risks of end-stage renal disease and mortality. Despite current therapies, its multifactorial pathogenesis limits effective renoprotection. Cellular senescence, a stable cell cycle arrest state representing an adaptive response to cumulative damage, emerges as a pivotal driver of DKD progression. Hyperglycemic environment directly interferes with cell cycle regulatory mechanisms or indirectly induces cell cycle arrest to accelerate renal cell senescence through various pathways, including mitochondrial dysfunction, impaired autophagy, endoplasmic reticulum stress, oxidative stress, disordered iron metabolism and inflammatory responses. This process ultimately compromises tissue repair mechanisms and exacerbates renal injury. The review systematically synthesizes current knowledge on the core biological hallmarks of cellular senescence and their mechanistic roles across key renal cell types (renal tubular epithelial cells, glomerular endothelial cells, mesangial cells and podocytes) in DKD pathogenesis. Furthermore, we evaluate emerging therapeutic strategies that target cellular senescence-associated pathways, with particular emphasis on the multi-target potential of natural products. By delineating the interplay between metabolic dysregulation and cellular senescence-driven renal decline, this work provides a foundational framework for developing novel interventions to halt DKD progression.
糖尿病肾病（DKD）是糖尿病最严重的微血管并发症之一，显著增加了终末期肾病和死亡风险。尽管有目前的治疗方法，但其多因素发病机制限制了有效的肾脏保护。细胞衰老，一种代表对累积损伤的适应性反应的稳定细胞周期停滞状态，成为DKD进展的关键驱动因素。高血糖环境直接干扰细胞周期调节机制，或间接诱导细胞周期停滞，通过各种途径加速肾细胞衰老，包括线粒体功能障碍、自噬受损、内质网应激、氧化应激、铁代谢紊乱和炎症反应。这一过程最终损害组织修复机制并加剧肾损伤。本综述系统地综合了目前关于细胞衰老的核心生物学特征及其在DKD发病机制中跨关键肾细胞类型（肾小管上皮细胞、肾小球内皮细胞、系膜细胞和足细胞）的机制作用的知识。此外，我们评估了针对细胞衰老相关途径的新兴治疗策略，特别强调天然产物的多靶点潜力。通过描绘代谢失调与细胞衰老驱动的肾脏衰退之间的相互作用，这项工作为开发阻止DKD进展的新型干预措施提供了一个基础框架。
