TSPO Mediates Tubulointerstitial Fibrosis and Kidney Inflammation After Unilateral Ureteral Obstruction

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Background: Tubulointerstitial fibrosis is a hallmark of chronic kidney disease (CKD) and predicts progression to kidney failure. A better understanding of its pathogenetic mechanisms is required for designing novel and effective treatments for this irreversible pathological process. Translocator protein (TSPO), located on the outer mitochondrial membrane, is associated with renal tubular cell death and regeneration in acute kidney injury. However, the role of TSPO in progressive CKD remains unknown. Methods: Unilateral ureteral obstruction (UUO) or sham operation were performed on C57BL/6J mice to establish progressive tubulointerstitial fibrosis. TSPO antagonist PK11195 or vehicle was administrated daily to UUO mice for 7 days starting on the day of surgery. Kidneys were harvested for histology, inflammation and fibrosis. Results: Histopathologically, tubular damage induced by UUO was reversed by PK11195 treatment. Induction of TNF-α, CCL-2 and IL-1β mRNA in the UUO kidney was reduced in PK11195 group compared to vehicle control. UUO-induced collagen deposition, as demonstrated by Masson's Trichrome and Picrosirius Red staining, was decreased after PK11195 treatment, and immunohistochemical analysis further confirmed significant reduction of Col-1 and Col-3 expression. Furthermore, PK11195 treatment downregulated UUO-induced fibronectin, α-SMA, vimentin and TGF-β levels by Western blotting. Conclusions: We provided novel data to show that blockade of TSPO activity could alleviate kidney fibrosis and inflammation in murine UUO, suggesting that TSPO could play an important role in regulating progressive kidney disease. Funding: Health and Medical Research Fund (HMRF) of Hong Kong (grant no. 09202356); Hong Kong Society of Nephrology Research Grant 2022 Funding: Government Support - Non-U.S.

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