Foxp3+调节性T细胞致病性转化在蛋白尿诱导的肾小管间质炎症中的作用研究

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.

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。

背景:近期研究显示miR-181a参与多种炎症相关疾病，但其参与糖尿病肾病(DN)发病机制尚不明确。在此，我们研究了miR-181a在DN患者及其动物模型中的作用和机制探讨。.方法:通过实时RT-PCR检测DN患者肾脏和DN小鼠模型db/db小鼠的miR-181a水平。通过荧光素酶报告基因分析，研究miR-181a与潜在靶基因转录本的3'-UTR的相互作用。miR-181a-GFP-aav和miR-181a inhibitor分别在db/db小鼠肾脏中过表达或下调miR-181a,检测肾组织靶基因发病机制和炎症的变化情况。.结果:表达分析显示DN患者和DN小鼠肾脏中miR-181a水平显著下降，导致促炎基因(肿瘤坏死因子-ɑ,IL-1β和IL-18)表达增多，抑制miR-181a加重这些变化,过表达miR-181a可减轻上述变化。在糖尿病肾病患者中，miR- 181a和肿瘤坏死因子-ɑ,IL-1β,IL-18呈负性相关。荧光素酶分析显示肿瘤坏死因子-ɑ是miR-181a的直接靶目标。.结论:我们的数据突出miR-181s通过靶向负性调控肿瘤坏死因子-ɑ的表达参与糖尿病肾病患者肾脏炎症的发生和发展。因此，miR-181a可能作为DN肾脏炎症的潜在治疗靶点。