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.
摘要：
肾间质纤维化（RIF）通常与炎性细胞浸润有关，没有有效的治疗方法。程序性死亡细胞-1（PD-1）及其配体PD-L1在T细胞共抑制和耗尽中起着关键作用，但在RIF中的作用尚不清楚。来自122名IgA肾病（IgAN）患者的血清数据分析显示，高水平的可溶性PD-1（sPD-1）是RIF和肾功能进展的独立危险因素。PD-L1在具有高水平sPD-1的IgAN患者和单侧输尿管梗阻（UUO）小鼠的肾间质组织中也过表达。在体外受炎症或缺氧刺激时，PD-L1在胶原蛋白和α-SMA上调的HK-2细胞中显著过表达。此外,在HK-2和jurkat细胞共培养系统中加入基质金属蛋白酶(MMP-2)可以提高培养上清液中sPD-1的水平,这表明IgAN的血清sPD-1可能被浸润到肾小管间质炎症微环境中的T细胞MMP-2裂解。至关重要的是，注射PD-L1融合蛋白，sPD-1阻断剂可以通过增加T细胞共抑制和耗竭来改善UUO小鼠的肾纤维化，提示PD-L1融合靶向治疗肾纤维化的潜力。一起拿,它揭示了血清中的sPD-1和肾间质组织的PD-L1在IgAN肾纤维化发展中的新因果作用，PD-L1融合蛋白靶向血清sPD-1是预防IgAN肾纤维化的潜在治疗方法。
