Abstract: FR-PO1211
Glutamine Metabolism Inhibition Alleviates Kidney Fibrosis through the Immunometabolic Axis
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Yang, Huang-Yu, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan
- Tsai, Chung Ying, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan
- Chen, Kuan-Hsing, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan
- Yang, Chih-Wei, Chang Gung Memorial Hospital Linkou, Taoyuan, Taiwan
Background
Chronic kidney disease manifests as a gradual loss of kidney function, which is partly attributed to fibrosis. An inflammatory response is elicited in a unilateral ureteral obstruction (UUO) model and contributes to kidney fibrosis. A glutamine antagonist, 6-diazo-5-oxonorleucine (DON), acts as an immune modulator. However, the role of glutamine metabolism in kidney fibrosis remains unclear.
Methods
Fibrosis induced by UUO is reduced in DON-treated mice than that in untreated mice. Single-cell RNA sequencing is used to characterize the effects of DON on immune and proximal tubule (PT) cells following UUO.
Results
DON induces oxidative stress in T cells infiltrating the kidney and skews the T cells toward regulatory phenotype via HIF-1α-KDM4C-ROS axis. Hypomethylation of the FOXP3 promoter occurred under glutamine deprivation with elevated levels of reactive oxygen species, a result of fatty acid β-oxidation and attenuated intracellular glutathione levels. Moreover, infiltrating macrophages show an Mmp12+ reparative phenotype. Patrolling monocytes decrease upon DON treatment. The percentage of aged neutrophils also increases, showing an apoptotic phenotype. DON alleviates UUO-induced hypoxia and increases oxidative phosphorylation in PT cells. DON-treated kidneys show reduced collagen and CD52 levels and upregulated the macrophage migration inhibitory factor communication pathway.
Conclusion
Hence, the inhibition of the glutamine pathway reduces kidney fibrosis after injury and can be exploited as a therapeutic strategy for chronic kidney fibrosis.