Deciphering Endoplasmic Reticulum Stress Activation and Its Role in Kidney Disease Progression via the STING Pathway

Background: Endoplasmic reticulum (ER) stress is crucial in the pathogenesis of kidney disease, yet the mechanisms initiating ER stress remain largely unexplored. Viruses are known to manipulate ER-related processes, potentially aiding their replication and pathogenesis. The adaptor molecule STING, which detects double-strand DNA in viral and bacterial infections, has also been implicated in sterile chronic kidney inflammation and may influence ER stress. Given these insights, we investigated the relationship between STING, ER stress, and the development of kidney disease. Methods: We utilized STING N153S mice, which exhibit constitutive STING activation, and mice with conditional STING deletion in kidney tubules. In vitro experiments included silencing of STING or ER stress pathways, and molecular events were analyzed through immunofluorescence, qPCR, Western blotting, and immunoprecipitation techniques. Gene expression data were scrutinized through RNA sequencing from human control and diseased samples, as well as mouse kidney disease models Results: In both cisplatin and UUO models, we observed consistent activation of STING and the ER stress–activated eIF2α kinase (PERK) pathway. STING was found to physically interact with and activate PERK in tubule cell, leading to ER stress and subsequent renal fibroinflammation. Conversely, deletion of STING or inhibition of PERK provided protection against disease development. sc-RNA-Seq and spatial transcriptomic analysis of human CKD patients and mouse kidney injury models reinforced the association between renal dysfunction and activation of the ER stress pathway. Conclusion: Our findings reveal a novel mechanism whereby STING activation triggers ER stress via the PERK pathway, resulting in kidney tubule injury and fibrosis. This breakthrough offers promising avenues for developing strategies to modulate ER stress and create effective therapies for fibroinflammatory kidney diseases. Funding: NIDDK Support