mechanistic link between the deficiency polycystin-1 and mitochondrial homeostasis and the activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)/stimulator of the interferon genes (STING) pathway. Our data identify cGAS as an important mediator of renal cystogenesis and suggest that its inhibition may be useful to slow down the disease progression. Background Immune cells significantly contribute to the progression of autosomal dominant polycystic kidney disease (ADPKD), the most common genetic disorder of the kidney caused by the dysregulation of the Pkd1 or Pkd2 genes. However, the mechanisms triggering the immune cells recruitment and activation are undefined. Methods Immortalized murine collecting duct cell lines were used to dissect the molecular mechanism of cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) activation in the context of genotoxic stress induced by Pkd1 ablation. We used conditional Pkd1 and knockout cGas−/− genetic mouse models to confirm the role of cGAS/stimulator of the interferon genes (STING) pathway activation on the course of renal cystogenesis. Results We show that Pkd1-deficient renal tubular cells express high levels of cGAS, the main cellular sensor of cytosolic nucleic acid and a potent stimulator of proinflammatory cytokines. Loss of Pkd1 directly affects cGAS expression and nuclear translocation, as well as activation of the cGAS/STING pathway, which is reversed by cGAS knockdown or functional pharmacological inhibition. These events are tightly linked to the loss of mitochondrial structure integrity and genotoxic stress caused by Pkd1 depletion because they can be reverted by the potent antioxidant mitoquinone or by the re-expression of the polycystin-1 carboxyl terminal tail. The genetic inactivation of cGAS in a rapidly progressing ADPKD mouse model significantly reduces cystogenesis and preserves normal organ function. Conclusions Our findings indicate that the activation of the cGAS/STING pathway contributes to ADPKD cystogenesis through the control of the immune response associated with the loss of Pkd1 and suggest that targeting this pathway may slow disease progression....

中文翻译：

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cGAS 激活加速常染色体显性多囊肾病的进展

多囊蛋白-1 缺乏与线粒体稳态以及环磷酸鸟苷-磷酸腺苷合酶 (cGAS)/干扰素基因刺激剂 (STING) 途径激活之间的机制联系。我们的数据表明 cGAS 是肾囊肿发生的重要介质，并表明其抑制可能有助于减缓疾病进展。背景 免疫细胞对常染色体显性多囊肾病 (ADPKD) 的进展有显着影响，ADPKD 是由 Pkd1 或 Pkd2 基因失调引起的最常见的肾脏遗传性疾病。然而，触发免疫细胞招募和激活的机制尚不清楚。方法 使用永生化小鼠集合管细胞系来剖析 Pkd1 消除引起的基因毒性应激背景下环磷酸鸟苷-磷酸腺苷合酶 (cGAS) 激活的分子机制。我们使用条件 Pkd1 和敲除 cGas−/− 基因小鼠模型来确认 cGAS/干扰素基因刺激剂 (STING) 通路激活在肾囊肿发生过程中的作用。结果我们发现 Pkd1 缺陷的肾小管细胞表达高水平的 cGAS，cGAS 是胞质核酸的主要细胞传感器，也是促炎细胞因子的有效刺激剂。 Pkd1 的缺失直接影响 cGAS 表达和核转位，以及 cGAS/STING 通路的激活，而 cGAS 敲低或功能性药理抑制可逆转这种激活。这些事件与线粒体结构完整性的丧失和 Pkd1 耗竭引起的基因毒性应激密切相关，因为它们可以通过有效的抗氧化剂线粒体醌或多囊蛋白-1 羧基末端尾部的重新表达来恢复。在快速进展的 ADPKD 小鼠模型中，cGAS 的基因失活显着减少了囊肿发生并保留了正常的器官功能。结论 我们的研究结果表明，cGAS/STING 通路的激活通过控制与 Pkd1 丢失相关的免疫反应来促进 ADPKD 囊肿发生，并表明针对该通路可能会减缓疾病进展。