蛋白尿不仅是肾脏疾病常见临床表现,也是促进CKD进展的重要因素。研究表明,蛋白尿通过引起肾间质炎症反应而介导纤维化形成,但详细机制仍不清楚。我们前期研究发现,蛋白负荷所致白蛋白尿能够引起肾小管上皮细胞产生大量炎症因子,导致肾小管间质炎症细胞浸润。最新研究发现,促炎因子存在的炎症微环境中,调节性T细胞(Treg)可能通过向Th17细胞发生致病性转化而加重炎症反应,但确切机制仍待阐明。本研究假说:蛋白尿可以引起肾小管上皮细胞分泌促炎症因子IL-1β,后者诱导Foxp3+ CD4+ Treg细胞转变为IL-17+Th17细胞,导致肾小管间质炎症损伤和纤维化形成。本研究拟通过模式动物和体外细胞培养 ,探讨Foxp3+Treg细胞在蛋白尿诱导的肾小管间质炎症中的作用,为临床防治CKD提供新策略和理论依据。

Proteinuria is not only an important marker of chronic kidney disease, but also a crucial contributor to chronic kidney disease(CKD). A number of studies have demonstrated that proteinuria could induce tubulointerstitial inflammation and TIF. However,the exact mechanisms have not been fully elucidated. Our previous study found that albuminuria induced the abnormal expression of pro-inflammatory cytokines by proximal tubular epithelial cells (PETCs) and pro-inflammatory cells infiltration in tubule interstitium. The most recent studies indicated that, under micro-inflammation conditions, Foxp3+CD4+ T cells lose Foxp3 expression and undergo transdifferentiation into Th17 cells, which contribute to the pathogenesis of tubulointerstitial inflammation. In this study, we hypothesized that proteinuria could promote tubulointerstitial injury by stimulating tubular epithelial cell to release pro-inflammatory cytokines, which subsequently induced Foxp3 positive regulatory T cells transdifferentiated into Th17 cells. We will use cell culture and animal models to demonstrate the role of Foxp3+Treg cells in tubulointerstitial inflammation. This study would provide a novel insight about the proteinuria in mediating the progression of chronic kidney disease.