Wu Zhiyuan, Zhou Yi, Yang Feng, Wang Luobing, Wu Feng, Liu Weiwei, Gao Jiandong
Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (20DZ2272200), Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Nephrology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China; TCM Institute of Kidney Disease, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai Key Laboratory of Traditional Chinese Clinical Medicine (20DZ2272200), Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Ethnopharmacol. 2025 Jul 24;351:120084. doi: 10.1016/j.jep.2025.120084. Epub 2025 Jun 9.
Shizhifang (SZF), a traditional Chinese herbal formula used at Shanghai Shuguang Hospital for over 20 years, has shown clinical efficacy in lowering serum uric acid (SUA) and protecting renal function.
To explore the mechanism by which SZF protects against hyperuricemia (HUA)-induced renal tubular epithelial cell injury, focusing on mitochondrial dysfunction mediated by Drp1.
RNA-seq was performed on HK2 cells to identify affected pathways. HUA rat and mouse models were used to assess renal function, oxidative stress, inflammation, and mitophagy. Key interventions included SZF, a Drp1 inhibitor, and autophagy modulators. In vitro, Drp1 knockdown HK2 cells were used to evaluate ROS, mitochondrial membrane potential (MMP), and proteins involved in mitochondrial dynamics and mitophagy.
SZF significantly reduced SUA, improved renal function, suppressed ROS and inflammation, and alleviated mitochondrial damage. RNA-seq revealed enrichment of ROS and mitophagy pathways. SZF and Drp1 inhibition restored MMP, reduced fission and mitophagy, and enhanced mitochondrial fusion. Combined SZF and Drp1 siRNA treatment showed superior efficacy.
SZF mitigates HUA-induced renal injury by inhibiting Drp1-mediated mitochondrial fission and mitophagy, promoting mitochondrial fusion, and reducing oxidative stress. These findings reveal a novel mitochondrial mechanism for SZF's reno-protective effect.
施之方（SZF）是上海曙光医院使用了20多年的一种传统中药配方，已显示出在降低血清尿酸（SUA）和保护肾功能方面的临床疗效。
探讨施之方预防高尿酸血症（HUA）诱导的肾小管上皮细胞损伤的机制，重点关注由动力相关蛋白1（Drp1）介导的线粒体功能障碍。
对HK2细胞进行RNA测序以确定受影响的信号通路。使用HUA大鼠和小鼠模型评估肾功能、氧化应激、炎症和线粒体自噬。关键干预措施包括施之方、一种Drp1抑制剂和自噬调节剂。在体外，使用Drp1基因敲低的HK2细胞评估活性氧（ROS）、线粒体膜电位（MMP）以及参与线粒体动力学和线粒体自噬的蛋白质。
施之方显著降低SUA水平，改善肾功能，抑制ROS和炎症，并减轻线粒体损伤。RNA测序显示ROS和线粒体自噬信号通路富集。施之方和Drp1抑制可恢复MMP，减少线粒体裂变和线粒体自噬，并增强线粒体融合。施之方与Drp1小干扰RNA联合处理显示出更好的疗效。
施之方通过抑制Drp1介导的线粒体裂变和线粒体自噬、促进线粒体融合以及减少氧化应激来减轻HUA诱导的肾损伤。这些发现揭示了施之方肾脏保护作用的一种新线粒体机制。
