Pei Zhenzhen, Chen Yupeng, Zhang Yang, Zhang Shan, Wen Zhige, Chang Ruiting, Ni Boran, Ni Qing
Department of Endocrinology, Guang' Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
Department of Endocrinology, Guang' Anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
Eur J Pharmacol. 2025 Mar 15;991:177289. doi: 10.1016/j.ejphar.2025.177289. Epub 2025 Jan 27.
Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide, and podocyte ferroptosis plays a crucial role in its pathogenesis. Hirsutine (HS) reduces blood glucose levels and improve insulin resistance in diabetic mice, suggesting its potential use in diabetes treatment. Here, we established a db/db mouse model of DKD and administered HS for 8 weeks. We found that HS decreased the concentrations of iron, reactive oxygen species (ROS), and malondialdehyde (MDA) in renal tissues. Furthermore, HS treatment restored mitochondrial morphology, increased Glutathione Peroxidase 4(GPX4) levels, and decreased p53 levels, alleviating podocyte loss in the DKD mouse model. However, the effects of HS were reversed by the p53 activator Nutlin-3. Therefore, we propose HS may mitigate podocyte injury in DKD by regulating the p53/GPX4 pathway, providing a novel strategy for targeting podocyte ferroptosis in DKD.
糖尿病肾病（DKD）是全球慢性肾病的主要病因，足细胞铁死亡在其发病机制中起关键作用。去甲氧基钩藤碱（HS）可降低糖尿病小鼠的血糖水平并改善胰岛素抵抗，提示其在糖尿病治疗中的潜在用途。在此，我们建立了DKD的db/db小鼠模型，并给予HS治疗8周。我们发现HS降低了肾组织中铁、活性氧（ROS）和丙二醛（MDA）的浓度。此外，HS治疗恢复了线粒体形态，提高了谷胱甘肽过氧化物酶4（GPX4）水平，并降低了p53水平，减轻了DKD小鼠模型中的足细胞损失。然而，p53激活剂Nutlin-3可逆转HS的作用。因此，我们提出HS可能通过调节p53/GPX4途径减轻DKD中的足细胞损伤，为靶向DKD中的足细胞铁死亡提供了一种新策略。
