Abstract: FR-PO1185
Knockdown of Translocator Protein (TSPO) Slows AKI to CKD Transition through Regulating Mitochondrial Dysfunction
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
- Feng, Yuchen, The University of Hong Kong, Hong Kong, Hong Kong
- Yiu, Wai Han, The University of Hong Kong, Hong Kong, Hong Kong
- Ma, Jingyuan, The University of Hong Kong, Hong Kong, Hong Kong
- Lai, Kar Neng, The University of Hong Kong, Hong Kong, Hong Kong
- Tang, Sydney, The University of Hong Kong, Hong Kong, Hong Kong
Background
Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Emerging studies suggest that mitochondrial dysfunction is a pivotal contributor to the transition from AKI to CKD. Translocator protein (TSPO), located on the outer mitochondrial membrane, is associated with kidney tubular cell death and regeneration in AKI. However, the role of TSPO in AKI to CKD transition remains unknown.
Methods
Kidney tubule-specific TSPO knockout (Tubule-TSPO-/-) mice were created by crossing TSPO floxed (TSPOflox/flox) mice on a C57BL/6J background with tamoxifen inducible Ksp-CreERT2 mice. Unilateral ischemia-reperfusion injury (uIRI) for different timepoints was performed on both Tubule-TSPO-/- and TSPOflox/flox wildtype mice to establish AKI to CKD transition. Kidneys were harvested for histology, inflammation, fibrosis and mitochondrial function measurements.
Results
Both TSPO mRNA and protein levels were increased at day 1 and lasted for at least 14 days after uIRI. Histopathologically, uIRI-induced tubular damage was reversed by knockdown of TSPO at day 7 and day 14. Induction of fibronectin, Col-1, TNF-α, CCL-2 and IL-1β mRNA in the uIRI kidney was reduced in knockout mice compared to control. In 14 day-uIRI mice, immunohistochemical analysis further confirmed significant reduction of Col-1 and Col-3 expression by TSPO depletion. Furthermore, PGC1-α, the master regulator of mitochondrial function, was significantly increased after knockdown of TSPO. Electron microscopy demonstrated a higher number of mitochondria and improved mitochondrial morphology with TSPO depletion. Reduction of mitochondrial DNA copy number by uIRI was also reversed by knockdown of TSPO.
Conclusion
Knockdown of TSPO in tubular cells could alleviate kidney inflammation and fibrosis in murine uIRI models, increase mitochondrial number and restore mitochondrial structure. The results suggested that TSPO could play an important role in regulating mitochondrial function during AKI to CKD transition progress.
Funding: Health and Medical Research Fund (HMRF) of Hong Kong (grant no. 09202356); Hong Kong Society of Nephrology Research Grant 2022