Abstract: FR-PO227
Renal Tubular Calcium Oxalate Crystals Induce Mitochondrial Damage and cGAS-STING Activation
Session Information
- Mineral Bone Disease: Transplant and Kidney Stones
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Sharpe, Elizabeth H., University of California Santa Barbara, Santa Barbara, California, United States
- Sharma, Shaina M., University of California Santa Barbara, Santa Barbara, California, United States
- Torres, Jacob A., University of California Santa Barbara, Santa Barbara, California, United States
- Weimbs, Thomas, University of California Santa Barbara, Santa Barbara, California, United States
Background
The kidney is subject to the formation of microscopic calcium oxalate (CaOx) crystals which can cause damage. Previous in vitro studies indicate that CaOx-induced damage involves mitochondrial dysfunction, but the specific pathways have yet to be elucidated.
The cGAS-STING pathway is a key regulator of the inflammatory response and fibrosis in acute kidney injury (AKI), and activation by cytosolic dsDNA leads to the production of pro-inflammatory cytokines. Activated STING recruits kinases TBK1 and IKK, resulting in activation of transcription factors IRF3 and NF-κB. Activation is triggered by both foreign and self-DNA, including mitochondrial DNA released after mitochondrial damage. Here, we found that mitochondrial damage and activation of the cGAS-STING pathways occurs following acute CaOx crystal deposition in wild type (WT) rats.
Methods
WT S.D. rats received 1 mg/kg sodium oxalate (NaOx) by intraperitoneal injection to induce acute CaOx crystal formation. Immunohistochemical and immunofluorescence staining was used to visualize protein localization in kidney sections at various time points post-injection.
Results
NaOx administration led to decreased mitochondrial HSP60 in renal epithelial cells (Figure 1A), indicative of mitochondrial damage. NaOx also promoted activation of downstream STING targets, including an increase in p-TBK1 and p-IRF3 (Figure 1B), as well as nuclear translocation of NF-κB (Figure 1C).
Conclusion
CaOx crystals promote mitochondrial damage and subsequent activation of the cGAS-STING pathway. Persistent CaOx crystal deposition as a form of subclinical AKI throughout life may drive renal functional decline.
Staining of kidneys from WT S.D. rats at indicated timepoints post-injection with NaOx or saline control (A) IF staining of HSP60 (B) IHC staining of p-IRF3, IRF3, and p-TBK1 (C) IF staining of of NF-κB