T Cell‐Independent Role of PD‐L1 in Kidney Repair: Mitigation of Tubular DNA Damage via PD‐L1/BRCA1 Interaction Following AKI

ABSTRACT 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.