Endoplasmic reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.

中文翻译：

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内质网应激和干扰素基因刺激因子 （STING） 通路在肾纤维化中的关键作用


内质网 （ER） 应激是 ER 不堪重负且无法正确管理其蛋白质负荷的情况。ER 应激在肾脏疾病中的确切激活机制和作用尚不清楚。为了研究这一点，我们进行了无偏倚的转录组学分析，以证明慢性肾病患者肾脏和急性和慢性肾损伤小鼠模型 （顺铂和单侧输尿管梗阻） 的 ER 应激，并重新分析了先前发表的关于叶酸和线粒体转录因子 A （TFAM） 敲除小鼠的数据。抑制 ER 应激的蛋白激酶 RNA 样 ER 激酶 （PERK） 臂但不激活转录因子 6 或肌醇需求酶 1，保护小鼠免受肾纤维化的影响。干扰素基因刺激物 （STING） 被确定为肾小管细胞中 ER 应激的重要上游激活剂。发现 STING 和 PERK 存在物理相互作用，STING 激动剂在肾小管细胞中诱导 PERK 激活。具有 STING 激活突变的小鼠表现为 ER 应激和肾纤维化炎症。我们还生成了具有肾小管特异性 STING 缺失的小鼠，这些小鼠对 ER 应激和肾纤维化具有抵抗力。人肾空间转录组学强调了 STING 、 ER 应激和纤维化基因表达之间的空间相关性。因此，我们的结果表明，STING 是肾纤维化发展过程中肾小管细胞中 PERK 和 ER 应激的重要上游调节因子。