MAVS在蛋白尿诱导的肾小管损伤中的作用及机制研究

Proteinuria has been identified as a contributor of renal tubular injury and chronic kidney disease progression with uncertain mechanisms. Emerging evidence indicated that an innate immunity-related molecule MAVS (Mitochondrial antiviral signaling) was highly expressed in kidney and inducible in kidney tissues of proteinuric patients and albumin-overloaded mice and in renal tubular cells treated with albumin. Meantime, overexpression of MAVS in renal tubular cells resulted in cell apoptosis and injury in line with the elevation of TRAF6, a protein related to the activation of NF-κB, and inflammatory cytokines, which suggested that MAVS/TRAF6/NF-κB may serve as a pathogenic pathway in mediating proteinuria-induced renal tubular injury. In addition, bioinformatics analysis showed two binding sites of transcription factor Oct-1 in MAVS promoter region. More importantly, when Oct-1 was overexpressed in renal tubular cells, MAVS expression was significantly enhanced. Thus we hypothesized that Oct-1-regulated MAVS might mediate proteinuria-induced renal tubular injury via promoting TRAF6/NF-κB signaling pathway. In the present proposal, employing the models of animal, cell and molecule, we will fully investigate the contribution of Oct-1/MAVS/TRAF6/NF-κB pathway in proteinuria-induced kidney injury, which will offer new insights into the therapies of proteinuria-related kidney injury.

蛋白尿可导致肾小管损伤、促进慢性肾脏病进展，但具体机制不明。线粒体抗病毒信号分子（MAVS）是介导天然免疫的重要接头蛋白，高表达于肾组织。我们前期研究发现蛋白尿患者肾脏、白蛋白负荷小鼠及白蛋白处理的肾小管上皮细胞（RTEC）中MAVS表达显著上调，过表达MAVS导致细胞凋亡并加重白蛋白诱导的RTEC损伤；同时高表达MAVS能上调NF-κB上游调节蛋白TRAF6及炎性因子的表达，提示蛋白尿可能通过MAVS/TRAF6/NF-κB通路介导炎症反应及肾小管损伤。进一步的生物信息学分析发现，转录因子Oct-1在MAVS启动子区有结合位点，而过表达Oct-1促进了MAVS转录。故推测：蛋白尿可能通过Oct-1调控MAVS表达，进而激活TRAF6/NF-κB通路诱发肾小管炎症性损伤。本课题将在动物、细胞和分子水平深入研究该通路在蛋白尿诱导肾小管损伤中的作用机制，为临床治疗蛋白尿相关的肾损伤提供新视点。

线粒体抗病毒信号分子（Mitochondrial antiviral signaling，MAVS）是位于RIG-I/MDA-5通路下游的重要接头蛋白，通过招募IRF3（Interferon regulatory factor 3）并诱导I型干扰素来发挥抗病毒作用。近年来有关MAVS的研究集中在免疫细胞抵御病毒感染方面。而也有研究发现，MAVS介导的级联反应参与非感染性疾病中炎症的发生与发展。然而MAVS在肾脏中的具体功能尚无明确研究，在蛋白尿诱导肾小管损伤中的作用亦无报道。本项目针对蛋白尿诱导的肾小管损伤，旨在探讨MAVS在该病理过程中的作用与机制。我们的研究发现，MAVS在蛋白尿患者与白蛋白负荷小鼠模型肾组织中表达显著上调；体内外过表达MAVS加剧白蛋白诱导的肾小管损伤；而干扰MAVS则明显缓解相关指标。进一步，抑制NF-kB能明显缓解过表达MAVS导致的细胞炎症反应。另外，我们初步探讨了白蛋白对MAVS的表达调控，推测白蛋白可能通过诱导转录因子Oct-1来激活MAVS的转录。本项目的完成有望为蛋白尿相关肾病的临床防治与新药研发提供新依据。