The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.

中文翻译：

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补体 C5a 通过破坏线粒体代谢敏捷性诱导糖尿病肾病肾损伤

糖尿病的后遗症包括微血管并发症，例如糖尿病肾病 (DKD)，其涉及与线粒体代谢敏捷性、炎症和纤维化中断相关的葡萄糖介导的肾损伤。我们探讨了先天免疫补体成分 C5a（一种炎症的有效介质）在临床和实验性糖尿病 DKD 发病机制中的作用。在糖尿病患者中证实了 C5a 活性的显着全身性升高；传统的肾脏保护剂并没有针对这种升高进行治疗。C5a 及其受体 (C5aR1) 在疾病过程的早期和在几种不同的糖尿病啮齿动物模型中出现明显的肾损伤之前被上调。小鼠中 C5aR1 的基因缺失赋予了对糖尿病诱导的肾损伤的保护。肾脏的转录组学分析揭示了糖尿病诱导的线粒体脂肪酸代谢通路下调。对脂质组学特征的询问揭示了糖尿病肾脏中异常的心磷脂重塑，这是线粒体结构和生物能量学被破坏的主要标志。C5aR1 (PMX53) 口服活性抑制剂的体内递送逆转了表型变化并使肾线粒体脂肪酸谱、心磷脂重塑和柠檬酸循环中间体正常化。人肾近端肾小管上皮细胞在体外暴露于 C5a 导致线粒体呼吸功能和活性氧产生的改变。