改良后的胡芦巴丸通过促进 PKM2 介导的线粒体动态平衡来保护糖尿病肾小球足细胞。
Modified Hu-lu-ba-wan protects diabetic glomerular podocytes via promoting PKM2-mediated mitochondrial dynamic homeostasis.
机构信息
Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
出版信息
Phytomedicine. 2024 Jan;123:155247. doi: 10.1016/j.phymed.2023.155247. Epub 2023 Dec 2.
BACKGROUND
Mitochondrial dysfunction is implicated in the progression of diabetic kidney disease (DKD). Damaged mitochondria produce excessive reactive oxygen species (ROS) that can cause apoptosis. Mitochondrial dynamics control the quality and function of mitochondria. Targeting mitochondrial dynamics may reduce ROS-induced apoptosis and improve renal injury in DKD. Modified Hu-lu-ba-wan (MHLBW) shows distinct clinical effects on DKD patients, which are related to its role in antioxidant stress modulation. However, the relevant mechanisms of MHLBW have not been clearly explored.
PURPOSE
This study was aimed to evaluate the therapeutic effects of MHLBW on spontaneous DKD mice and clarify the potential mechanisms.
METHODS
The main components of MHLBW were identified by HPLC. Using db/db mice as DKD models, we evaluated the therapeutic effects of MHLBW on mice after an 8-week administration. We investigated the molecular mechanism of MHLBW in regulating mitochondrial dynamic homeostasis, podocyte apoptosis, and glomerular damage. After that, computational docking analysis and in vitro experiments were conducted for further mechanism verification.
RESULTS
Intragastric administration of MHLBW for 8 weeks in db/db mice significantly improved glucose metabolism, basement membrane thickening, mesangial expansion, glomerular fibrosis, and podocyte injury. MHLBW can reverse podocyte apoptosis via promoting mitochondrial dynamic homeostasis, which was related to regulating the PKM2/ PGC-1α/Opa1 pathway. Berberine (BBR), one of the components of MHLBW, exhibited preeminent affinity with PKM2 as reflected by computational docking analysis. In cultured podocytes, BBR can also prevent apoptosis by promoting PKM2-mediated mitochondrial dynamic homeostasis.
CONCLUSION
Our study demonstrates that MHLBW can treat DKD by inhibiting glomerular damage and podocyte apoptosis through positive regulation of PKM2-mediated mitochondrial dynamic homeostasis. These results may provide a potential strategy against DKD.
背景
线粒体功能障碍与糖尿病肾病（DKD）的进展有关。受损的线粒体产生过多的活性氧（ROS），可导致细胞凋亡。线粒体动力学控制着线粒体的质量和功能。靶向线粒体动力学可能会减少 ROS 诱导的细胞凋亡，改善 DKD 中的肾损伤。改良后的虎杖八味丸（MHLBW）对 DKD 患者具有明显的临床疗效，这与其在抗氧化应激调节中的作用有关。然而，MHLBW 的相关机制尚未得到明确探讨。
目的
本研究旨在评估 MHLBW 对自发性 DKD 小鼠的治疗作用，并阐明其潜在机制。
方法
采用高效液相色谱法（HPLC）鉴定 MHLBW 的主要成分。以 db/db 小鼠作为 DKD 模型，给予 MHLBW 治疗 8 周后，评估其对小鼠的治疗作用。我们研究了 MHLBW 调节线粒体动态平衡、足细胞凋亡和肾小球损伤的分子机制。之后，进行了计算对接分析和体外实验，以进一步验证机制。
结果
给予 db/db 小鼠 MHLBW 灌胃 8 周，可显著改善葡萄糖代谢、基底膜增厚、系膜扩张、肾小球纤维化和足细胞损伤。MHLBW 可通过促进线粒体动态平衡来逆转足细胞凋亡，这与调节 PKM2/PGC-1α/Opa1 通路有关。MHLBW 的成分之一黄连素（BBR）通过计算对接分析显示与 PKM2 具有卓越的亲和力。在培养的足细胞中，BBR 也可以通过促进 PKM2 介导的线粒体动态平衡来防止细胞凋亡。
结论
本研究表明，MHLBW 可通过正向调节 PKM2 介导的线粒体动态平衡来抑制肾小球损伤和足细胞凋亡，从而治疗 DKD。这些结果可能为 DKD 的防治提供潜在策略。
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