Abstract: FR-PO1076
Stimulator of Interferon Genes (STING) Mediates Endoplasmic Reticulum Stress Activation Causing Renal Fibroinflammation
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Silva, Magaiver Andrade, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Dhillon, Poonam, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Sanchez Navarro, Andrea, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Hu, Hailong, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Bergeson, Andrea Marie, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Miner, Jonathan J., University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Group or Team Name
- Susztak Lab.
Background
Endoplasmic reticulum (ER) stress plays a pivotal role in kidney disease pathogenesis, yet the mechanisms leading to ER stress are largely unexplored. Viruses are known to manipulate ER-related processes, potentially aiding their replication or pathogenesis. The adaptor molecule STING, known for detecting double-strand DNA in pathogenic infections. In light of these insights, we investigated the relationship between STING, ER stress, and the development of kidney disease.
Methods
We utilized STING N153S mice, exhibiting constitutive STING activation, and mice with a conditional deletion of STING from kidney tubules. We performed in vitro experiments, including the silencing of STING or ER stress pathways, and analyzed molecular events through immunofluorescence, qPCR, western blot, and immunoprecipitation techniques. Gene expression data was scrutinized through RNA sequencing from human control and diseased samples, as well as mouse kidney disease models.
Results
In both the cisplatin and UUO models, we identified a consistent activation of STING and the ER stress–activated eIF2α kinase (PERK) pathway. Interestingly, STING was found to physically interact with and activate PERK, leading to ER stress and, subsequently, renal fibroinflammation. On the contrary, deletion of STING or PERK inhibition showed a protective effect against disease development. Further, transcriptomic analysis of human CKD patients and mouse kidney injury models bolstered the association between renal dysfunction and ER stress pathway activation.
Conclusion
Our findings unveil a novel mechanism wherein STING activation triggers ER stress via the PERK pathway, leading to kidney tubule injury and fibrosis. This breakthrough research offers promising avenues for devising strategies to modulate ER stress and develop potent therapies for treating fibroinflammatory kidney diseases.
Funding
- NIDDK Support