Abstract: FR-PO965
STING Facilitates Renal Fibrosis Induced by Ischemia-Reperfusion Injury Through Regulation of Glycolysis
Session Information
- CKD: Pathobiology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Author
- Jiang, Anni, Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
Background
Renal fibrosis is the main pathological manifestation of chronic kidney disease (CKD). Studies have shown that the hypoxic microenvironment caused by ischemia-reperfusion injury (IRI) plays a key role in the progression of CKD, but the specific mechanism is not clear. A recent research hotspot, stimulator of interferon genes (STING), has been shown to have an important role in immune and inflammatory responses associated with kidney diseases, and its functional significance in the field of CKD remains poorly understood. Our aim was to investigate the role and mechanism of STING in IRI-associated renal fibrosis.
Methods
Wild-type C57BL/6J male mice were selected to interfere with the expression of STING by renal injection of STING lentivirus and intraperitoneal injection of STING inhibitor C-176. The model of IRI was established by unilateral renal pedicle clamping, and the mice were euthanized 7 days after reperfusion. In vitro, human kidney 2 (HK2) transfected with STING lentivirus were stimulated by hypoxia for 48 hours. Blood was collected from mice for serum biochemistry, and kidney tissue and HK2 cells were collected to detect the expression of STING and glycolysis changes (extracellular acidification rate, hexokinase activity and phosphofructokinase activity). The interaction of STING and its downstream interferon regulatory factor 3 (IRF3) with 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) was detected by immunoprecipitation.
Results
The expression of STING increased significantly in the model of renal fibrosis induced by IRI. In vitro, hypoxic stimulation caused epithelial mesenchymal transformation (EMT) in HK2 cells with concomitant upregulation of STING expression. Seven days after IRI, fibrosis markers and glycolysis levels were less elevated in the kidneys of mice with inhibited STING expression than in those of wild-type mice. Immunoprecipitation showed that STING/IRF3 interacted with PFKFB3 and that inhibition of STING expression in HK2 cells reduced the level of hypoxia-induced glycolysis and blocked EMT.
Conclusion
STING activated in hypoxic environment regulates the level of glycolysis through IRF3/PFKFB3 pathway, which leads to EMT in renal tubular epithelial cells and promotes the progression of renal fibrosis. Down-regulation of STING attenuates IRI-induced renal fibrosis by inhibiting the level of glycolysis.
Funding
- NIDDK Support