Coenzyme Q10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in unilateral ureteral obstruction

•CoQ10 ameliorates renal fibrosis by suppressing RIP1-RIP3-MLKL-mediated necroinflammation.•CoQ10 treatment attenuates oxidative stress and apoptotic cell death.•Preservation of ER and mitochondria fitness may be responsible for the renoprotective properties of CoQ10. 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. 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 Wnt3α/β-catenin/GSK-3β signaling·H2O2-exposed human kidney (HK-2) cells were also examined after treatment with CoQ10 or an RIP inhibitor. 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 Wnt3α/β-catenin/GSK-3β 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/β-catenin inhibitor ICG-001 deactivated H2O2-stimulated activation of Wnt3α/β-catenin/GSK-3β signaling. These findings suggest that CoQ10 attenuates renal fibrosis by inhibiting RIP1-RIP3-MLKL-mediated necroinflammation via Wnt3α/β-catenin/GSK-3β signaling in UUO.