Zang Nan, Cui Chen, Guo Xinghong, Song Jia, Hu Huiqing, Yang Mengmeng, Xu Mingyue, Wang Lingshu, Hou Xinguo, He Qin, Sun Zheng, Wang Chuan, Chen Li
Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China.
iScience. 2022 Sep 16;25(10):105145. doi: 10.1016/j.isci.2022.105145. eCollection 2022 Oct 21.
Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or TBK1 alleviates podocyte injury and improves renal functions in cultured podocytes or mouse models of diabetes and obesity. These results suggest that the mtDNA-cGAS-STING pathway promotes podocyte injury and is a potential therapeutic target for DKD or other obesity-related kidney diseases.
糖尿病肾病（DKD）是终末期肾病的主要病因。DKD尚无有效的治疗方法。在肾功能障碍的早期，足细胞中的cGAS-STING通路被激活，这与STING下游效应分子TBK1和NF-κB的激活有关，但与IRF3无关。脂毒性通过足细胞中的Bcl-2相关X蛋白（BAX）诱导线粒体损伤和mtDNA泄漏到细胞质中。BAX介导的mtDNA胞质泄漏在没有脂毒性的情况下可激活cGAS-STING通路，并且足以导致足细胞损伤。细胞质mtDNA的消耗、STING基因敲低或STING或TBK1的药理学抑制可减轻足细胞损伤，并改善糖尿病和肥胖症培养足细胞或小鼠模型中的肾功能。这些结果表明，mtDNA-cGAS-STING通路促进足细胞损伤，是DKD或其他肥胖相关肾病的潜在治疗靶点。
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