T Cell-Independent Role of PD-L1 in Kidney Repair: Mitigation of Tubular DNA Damage via PD-L1/BRCA1 Interaction...

Acute kidney injury (AKI) occurs in the patients undergoing anti-programmed cell death protein 1-ligand 1 (PD-L1) therapy, indicating that PD-L1 may play a critical role in maintaining renal homeostasis. However, the precise role and mechanism of PD-L1 in AKI remains largely elusive. In this study, we found that PD-L1 was primarily expressed in proximal tubules and significantly upregulated in both murine models of AKI and renal biopsy samples from AKI patients. Genetic specific deletion of PD-L1 in mouse tubular epithelial cells (TECs) exacerbated renal injury in ischemia-reperfusion injury-induced AKI. Mechanistically, PD-L1 was found to interact with BRCA1 and increase BRCA1 expression to safeguard TECs against DNA damage, thereby promoting cellular proliferation and suppressing apoptosis. To translate these findings into a potential therapeutic strategy, we developed a CGA-functionalized extracellular vesicle delivery system for targeted delivery of PD-L1 to injured TECs. This system efficiently restored PD-L1 expression and alleviated DNA damage of TECs in both TEC-specific PD-L1 knockdown and T-cell knockout AKI mouse models. Collectively, these findings uncover a novel function of PD-L1 in promoting adaptive TEC repair through BRCA1 interaction, independent of its canonical immunomodulatory function of T cells, and suggest that PD-L1 supplementation may represent a promising therapeutic strategy for AKI.