Department of Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400016, China.
College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing 400016, China.
Int Immunopharmacol. 2024 Nov 15;141:112794. doi: 10.1016/j.intimp.2024.112794. Epub 2024 Aug 12.
In China, the Astragalus membranaceus root is used to treat chronic kidney disease. Astragaloside IV (AS-IV), the primary bioactive compound, exhibits anti-inflammatory and antioxidative properties; however, its renoprotective mechanism in diabetic kidney disease (DKD) remains unclear. The study aimed to investigate the protective effects of AS-IV on DKD revealing the underlying mechanisms. We established an early diabetic rat model by feeding a high-fat diet and administering low-dose streptozotocin. Twelve weeks post-treatment, renal function was evaluated using functional assays, histological analyses, immunohistochemistry, western blotting, and transmission electron microscopy. HK-2 cells exposed to high glucose conditions were used to examine the effect of AS-IV on oxidative stress, iron levels, reactive oxygen species (ROS), and lipid peroxidation. Network pharmacology, proteomics, molecular docking, and molecular dynamics simulation techniques were employed to elucidate the role of AS-IV in DKD. The results revealed that AS-IV effectively enhanced renal function and mitigated disease pathology, oxidative stress, and ferroptosis markers in DKD rats. In HK-2 cells, AS-IV lowered the levels of lipid peroxides, Fe, and glutathione, indicating the repair of ferroptosis-related mitochondrial damage. AS-IV reduced mitochondrial ROS while enhancing mitochondrial membrane potential and ATP production, indicating its role in combating mitochondrial dysfunction. Overall, in silico analyses revealed that AS-IV interacts with HMOX1, FTH1, and TFR1 proteins, supporting its efficacy in alleviating renal injury by targeting mitochondrial dysfunction and ferroptosis. AS-IV may play a renoprotective role by regulating mitochondrial dysfunction and inhibiting. HMOX1/FTH1/TFR1-induced ferroptosis. Accordingly, AS-IV could be developed for the clinical treatment of DKD-related renal injury.
在中国，黄芪根被用于治疗慢性肾病。黄芪甲苷（AS-IV）是主要的生物活性化合物，具有抗炎和抗氧化作用；然而，其在糖尿病肾病（DKD）中的肾保护机制尚不清楚。本研究旨在探讨 AS-IV 对 DKD 的保护作用及其潜在机制。我们通过给予高脂肪饮食和低剂量链脲佐菌素建立早期糖尿病大鼠模型。治疗 12 周后，通过功能测定、组织学分析、免疫组织化学、蛋白质印迹和透射电子显微镜评估肾功能。使用高糖条件下暴露的 HK-2 细胞来研究 AS-IV 对氧化应激、铁水平、活性氧（ROS）和脂质过氧化的影响。采用网络药理学、蛋白质组学、分子对接和分子动力学模拟技术阐明 AS-IV 在 DKD 中的作用。结果表明，AS-IV 可有效改善 DKD 大鼠的肾功能，减轻疾病病理、氧化应激和铁死亡标志物。在 HK-2 细胞中，AS-IV 降低了脂质过氧化物、Fe 和谷胱甘肽的水平，表明其对铁死亡相关的线粒体损伤具有修复作用。AS-IV 降低了线粒体 ROS，同时增强了线粒体膜电位和 ATP 生成，表明其在对抗线粒体功能障碍方面发挥作用。总体而言，通过网络药理学分析，AS-IV 与 HMOX1、FTH1 和 TFR1 蛋白相互作用，支持其通过靶向线粒体功能障碍和铁死亡来缓解肾损伤的疗效。AS-IV 可能通过调节线粒体功能障碍和抑制 HMOX1/FTH1/TFR1 诱导的铁死亡发挥肾保护作用。因此，AS-IV 可用于开发治疗 DKD 相关肾损伤的临床应用。
