Coenzyme Q10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in unilateral ureteral obstruction
Coenzyme Q10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in unilateral ureteral obstruction
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DOI：
10.1016/j.intimp.2022.108868
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发表时间：
2022-05-26
影响因子：
5.6
通讯作者：
Li, Can
中科院分区：
文献类型：
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作者：
Jiang, Yu Ji;Jin, Jian;Li, Can
目的：辅酶 Q10 (CoQ10) 可以防止各种类型的损伤，但其在预防慢性肾脏病中肾脏疤痕形成方面的作用仍然是一个悬而未决的问题。在此，我们在单侧输尿管梗阻 (UUO) 大鼠模型和体外评估了 CoQ10 是否通过干扰坏死性炎症来减轻肾纤维化。 方法：患有 UUO 的大鼠每天接受 CoQ10 或 RIP 抑制剂（necrostatin-1 或 GSK872）治疗，持续 7 天。通过组织病理学和基因表达、氧化应激、细胞内细胞器、细胞凋亡分析评估 CoQ10 对 UUO 引起的肾损伤的影响，并在用 CoQ10 或 RIP 抑制剂处理后检查 Wnt3 α/β-catenin/GSK-3 beta 信号中心点 H2O2 暴露的人肾 (HK-2) 细胞。 RIP1-RIP3-MLKL 轴蛋白、NLRP3 炎性体的激活以及肾纤维化的演变。 UUO 诱导的氧化应激引起过度的内质网应激和线粒体功能障碍，从而通过 Wnt3 α/β-连环蛋白/GSK-3 β 信号传导引发细胞凋亡。 CoQ10 或 RIP 抑制剂可以减轻所有这些影响。在 H2O2 处理的 HK-2 细胞中，CoQ10 或 RIP 抑制剂抑制 RIP1-RIP3-MLKL 蛋白和焦亡相关细胞因子的表达，并阻碍细胞内活性氧的产生，如 MitoSOX 红染色和凋亡细胞死亡所示，但增加了细胞活力。 CoQ10 或 Wnt/β-连环蛋白抑制剂 ICG-001 使 H2O2 刺激的 Wnt3 α/β-连环蛋白/GSK-3 β 信号传导失活。结论：这些研究结果表明，CoQ10 通过 UUO 中的 Wnt3 α/β-连环蛋白/GSK-3 β 信号传导抑制 RIP1-RIP3-MLKL 介导的坏死性炎症，从而减轻肾纤维化。
Objective: Coenzyme Q10 (CoQ10) protects against various types of injury, but its role in preventing renal scarring in chronic kidney disease remains an open question. Herein, we evaluated whether CoQ10 attenuates renal fibrosis by interfering with necroinflammation in a rat model of unilateral ureteral obstruction (UUO) and in vitro.Methods: Rats with UUO were treated daily with CoQ10 or an RIP inhibitor (necrostatin-1 or GSK872) for 7 days. The influence of CoQ10 on renal injury caused by UUO was evaluated by histopathology and analysis of gene expression, oxidative stress, intracellular organelles, apoptosis, and Wnt3 alpha/beta-catenin/GSK-3 beta signaling center dot H2O2-exposed human kidney (HK-2) cells were also examined after treatment with CoQ10 or an RIP inhibitor.Results: UUO induced marked renal tubular necrosis, upregulation of RIP1-RIP3-MLKL axis proteins, activation of the NLRP3 inflammasome, and evolution of renal fibrosis. UUO-induced oxidative stress evoked excessive endoplasmic reticulum stress and mitochondrial dysfunction, which triggered apoptotic cell death through Wnt3 alpha/beta-catenin/GSK-3 beta signaling. All of these effects were mitigated by CoQ10 or an RIP inhibitor. In H2O2-treated HK-2 cells, CoQ10 or an RIP inhibitor suppressed the expression of RIP1-RIP3-MLKL proteins and pyroptosis-related cytokines, and hindered the production of intracellular reactive oxygen species as shown by MitoSOX Red staining and apoptotic cell death but increased cell viability. The CoQ10 or Wnt/beta-catenin inhibitor ICG-001 deactivated H2O2-stimulated activation of Wnt3 alpha/beta-catenin/GSK-3 beta signaling.Conclusion: These findings suggest that CoQ10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3 alpha/beta-catenin/GSK-3 beta signaling in UUO.