Immune checkpoint activity exacerbate renal interstitial fibrosis progression by enhancing PD-L1 expression in renal tubular epithelial cells.
Transl Res
; 271: 52-67, 2024 Sep.
Article
in En
| MEDLINE
| ID: mdl-38723861
ABSTRACT
Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Fibrosis
/
Epithelial Cells
/
B7-H1 Antigen
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Kidney Tubules
Limits:
Adult
/
Animals
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Female
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Humans
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Male
/
Middle aged
Language:
En
Journal:
Transl Res
Journal subject:
MEDICINA
/
TECNICAS E PROCEDIMENTOS DE LABORATORIO
Year:
2024
Type:
Article
Affiliation country:
China