Inhibition of PD-L1 in tubular epithelial cells attenuates renal fibrosis by suppressing TGFβR1 and FZD6 signaling.

Renal fibrosis represents the final common pathway in the progression of chronic kidney disease (CKD), yet the molecular mechanisms driving this process remain incompletely defined. While Programmed death ligand 1 (PD-L1) is a well-characterized immune checkpoint, its non-immune functions in chronic renal fibrosis have not been fully characterized. Here, we employed murine models of unilateral ureteral obstruction (UUO) and folic acid-induced nephropathy (FAN) in both wild-type and global Cd274 (PD-L1)-deficient mice to delineate the role of PD-L1 in renal fibrogenesis. Our data suggest that pharmacological PD-1/PD-L1 blockade or genetic ablation of PD-L1 significantly ameliorated tubular injury, reduced interstitial fibrosis, and preserved renal function in both models within the observed time windows of both models. Consistently, PD-L1 knockdown or blockade in TGF-β1-stimulated HK-2 cells attenuated the expression of profibrotic markers by suppressing TGF-β1/Smad3 and Wnt/β-catenin signaling. Mechanistically, PD-L1 was found to associate with TGFBR1 mRNA and FZD6 mRNA, correlating with stabilized transcript levels and facilitated expression, thereby amplifying their downstream signaling. Furthermore, bone marrow transplantation experiments revealed that PD-L1 deficiency in hematopoietic cells failed to mitigate fibrosis, suggesting the pathogenic role of intrinsic renal tubular PD-L1. Collectively, these findings highlight PD-L1 as a potential regulator of fibrotic signaling and a promising therapeutic target for halting CKD progression.