Soluble PD-1 drives renal fibrosis in CKD by disrupting immune homeostasis: Therapeutic mitigation via a targeted sPD-1 sequestration strategy

  • Life Sci. 2026 Jun 27:402:124556. doi: 10.1016/j.lfs.2026.124556.
Yuting Zhang  1 ,  Hongbin Peng  1 ,  Xue Mi  2 ,  Jipeng Li  1 ,  Yang Zha  1 ,  Mengting Wu  1 ,  Xiaomeng Xu  1 ,  Fang Zhao  3 ,  Haichao Cao  4 ,  Ye Chen  1 ,  Rui Lu  1 ,  Ya Zhao  5 ,  Guodong Yang  6 ,  Lijie He  7
Affiliations
  • 1. Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
  • 2. Department of Nephrology, 3201 Hospital, Hanzhong City, Shaanxi Province, China.
  • 3. Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China; Graduate School of Xi'an Medical University, Xi'an, China.
  • 4. Department of Nephrology, Xijing 986 Hospital, The Fourth Military Medical University, Xi'an, China.
  • 5. Department of Medical Microbiology and Parasitology, The Fourth Military Medical University, Xi'an, China. Electronic address: [email protected].
  • 6. Department of Biochemistry and Molecular Biology, The Fourth Military Medical University, Xi'an, China. Electronic address: [email protected].
  • 7. Department of Nephrology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. Electronic address: [email protected].
PMID: 42364692 DOI: 10.1016/j.lfs.2026.124556
Abstract

Aims: Renal interstitial fibrosis (RIF) drives chronic kidney disease (CKD) progression, with elevated soluble PD-1 (sPD-1) exacerbating chronic inflammation. This study aims to elucidate the pathogenic role of sPD-1 in RIF and evaluate "Exo-PD1"-a novel engineered extracellular vesicle strategy designed to sequester circulating sPD-1-as a targeted therapeutic intervention to mitigate renal fibrosis.

Materials and methods: We analyzed serum and renal biopsy samples from clinical CKD cohorts and three distinct mouse models-unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI), and aristolochic acid I (AAI)-induced nephropathy-using ELISA, immunohistochemistry, and flow cytometry. Exo-PD1 was engineered by surface-functionalizing extracellular vesicles with avidin to load anti-PD-1 antibodies. The therapeutic efficacy and safety profiles of Exo-PD1 were systematically evaluated in vitro and in vivo.

Key findings: Elevated sPD-1 strongly correlated with RIF severity and T-cell hyperactivation in both patients and murine models, while exogenous sPD-1 exacerbated fibrosis. Exo-PD1 effectively sequestered circulating sPD-1, outperforming conventional antibodies through local adsorption. Furthermore, Exo-PD1 treatment significantly attenuated T-cell hyperactivation, blunted inflammatory responses, and reduced key fibrotic markers (α-SMA, Collagen I) across models with minimal systemic toxicity.

Significance: sPD-1 acts as a critical mediator of renal fibrosis by disrupting immune homeostasis. The biocompatible Exo-PD1 platform effectively intercepts circulating sPD-1, disrupting the inflammation-fibrosis crosstalk and offering a highly translational therapeutic approach to halt CKD progression.

Keywords
Exosome; PD-1/PD-L1; Renal fibrosis; T-cell activation; sPD-1.
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