Sun Jia, Zhu Haiping, Wang Xiaorong, Gao Qiuqi, Li Zhuoying, Huang Huiya
Departmentof Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.
J Endocrinol. 2019 Mar;240(3):445-465. doi: 10.1530/JOE-18-0578.
The molecular signaling mechanisms of Coenzyme Q10 (CoQ10) in diabetic nephropathy (DN) remain poorly understood. We verified that mitochondrial abnormalities, like defective mitophagy, the generation of mitochondrial reactive oxygen species (mtROS) and the reduction of mitochondrial membrane potential, occurred in the glomerulus of db/db mice, accompanied by reduced PINK and parkin expression and increased apoptosis. These changes were partially reversed following oral administration of CoQ10. In inner fenestrated murine glomerular endothelial cells (mGECs), high glucose (HG) also resulted in deficient mitophagy, mitochondrial dysfunction and apoptosis, which were reversed by CoQ10. Mitophagy suppression mediated by Mdivi-1 or siPINK abrogated the renoprotective effects exerted by CoQ10, suggesting a beneficial role for CoQ10-restored mitophagy in DN. Mechanistically, CoQ10 restored the expression, activity and nuclear translocation of Nrf2 in HG-cultured mGECs. In addition, the reduced PINK and parkin expression observed in HG-cultured mGECs were partially elevated by CoQ10. CoQ10-mediated renoprotective effects were abrogated by the Nrf2 inhibitor ML385. When ML385 abolished mitophagy and the renoprotective effects exerted by CoQ10, mGECs could be rescued by treatment with mitoTEMPO, which is a mtROS-targeted antioxidant. These results suggest that CoQ10, as an effective antioxidant in mitochondria, exerts beneficial effects in DN via mitophagy by restoring Nrf2/ARE signaling. In summary, CoQ10-mediated mitophagy activation positively regulates DN through a mechanism involving mtROS, which influences the activation of the Nrf2/ARE pathway.
辅酶Q10（CoQ10）在糖尿病肾病（DN）中的分子信号传导机制仍未完全明确。我们证实，db/db小鼠肾小球中存在线粒体异常，如线粒体自噬缺陷、线粒体活性氧（mtROS）生成以及线粒体膜电位降低，同时伴有PINK和帕金蛋白表达减少以及细胞凋亡增加。口服CoQ10后，这些变化部分得到逆转。在有窗孔的小鼠肾小球内皮细胞（mGECs）中，高糖（HG）也会导致线粒体自噬缺陷、线粒体功能障碍和细胞凋亡，而CoQ10可使其逆转。由Mdivi-1或siPINK介导的线粒体自噬抑制消除了CoQ10发挥的肾脏保护作用，表明CoQ10恢复的线粒体自噬在DN中具有有益作用。从机制上讲，CoQ10恢复了HG培养的mGECs中Nrf2的表达、活性和核转位。此外，CoQ10部分提高了HG培养的mGECs中观察到的PINK和帕金蛋白表达降低。Nrf2抑制剂ML385消除了CoQ10介导的肾脏保护作用。当ML385消除CoQ10的线粒体自噬和肾脏保护作用时，用线粒体靶向抗氧化剂mitoTEMPO处理可挽救mGECs。这些结果表明，CoQ10作为线粒体中的一种有效抗氧化剂，通过恢复Nrf2/ARE信号传导，经由线粒体自噬在DN中发挥有益作用。总之，CoQ10介导的线粒体自噬激活通过涉及mtROS的机制对DN产生正向调节作用，mtROS影响Nrf2/ARE途径的激活。
