A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury

• Published in: International journal of molecular sciences Vol. 22; no. 24; p. 13304
• Main Authors: Liu, Jun, Yang, David C, Zhang, Jun, Hsu, Ssu-Wei, Weiss, Robert H, Chen, Ching-Hsien
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10-12-2021; MDPI
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - therapy; AKI; Animals; Apoptosis; B7-H1 Antigen - biosynthesis; B7-H1 Antigen - genetics; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cisplatin - pharmacology; Creatinine; Disease Models, Animal; Drug dosages; Epithelial cells; Epithelial Cells - metabolism; Epithelium; Gene Transfer Techniques; Immune checkpoint; Immune system; inflammation; Kidney Tubules, Proximal - metabolism; Kidneys; L1 gene; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Mice; Microenvironments; Pathogenesis; PD-L1 protein; Proteins; renal tubules; Spleen; T cells; Up-Regulation; T cells; inflammation; renal tubules; immune checkpoint; AKI
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222413304

The innate and adaptive immunities have been documented to participate in the pathogenesis of nephrotoxic acute kidney injury (AKI); however, the mechanisms controlling these processes have yet to be established. In our cisplatin-induced AKI mouse model, we show pathological damage to the kidneys, with the classical markers elevated, consistent with the response to cisplatin treatment. Through assessments of the components of the immune system, both locally and globally, we demonstrate that the immune microenvironment of injured kidneys was associated with an increased infiltration of CD4+ T cells and macrophages concomitant with decreased Treg cell populations. Our cell-based assays and animal studies further show that cisplatin exposure downregulated the protein levels of programmed death-ligand 1 (PD-L1), an immune checkpoint protein, in primary renal proximal tubular epithelial cells, and that these inhibitions were dose-dependent. After orthotopic delivery of PD-L1 gene into the kidneys, cisplatin-exposed mice displayed lower levels of both serum urea nitrogen and creatinine upon PD-L1 expression. Our data suggest a renoprotective effect of the immune checkpoint protein, and thereby provide a novel therapeutic strategy for cisplatin-induced AKI.