系膜细胞活化和免疫炎症的发生发展机制及干细胞调控

Mesangial proliferative glomerulonephritis is the main cause of uremia，which was mainly focused on the downstream stages of proliferation and sclerosis in previous studies. In this project, which is on the basis of a previous key program of national natural science foundation of China, we move the “research window” forward to focus on the upstream stages in which the pathogenic factors such as anti-Thy1 antibodies and IgA immune complex activate the mesangial cells and initiate inflammatory responses. In order to explore the key molecules, phenotypic change and molecular marker of mesangial cell activation, mesangial cell’s biological effects after the activation and the affection of cross talk between mesangial cells, endothelial cells and immune cells on mesangial immune inflammation, clarify the key molecules and signaling pathways of anti-Thy1 antibodies activating mesangial cells, verify the activation biomarker of mesangial cells obtained from vitro and vivo experiments in specimens of patients with mesangial proliferative IgA nephropathy, then raise the academic point of “the activated mesangial cell is a special kind of immune inflammatory cells”. In our study, the foxd1+ mesangial cell is used as the renal stem (progenitor) cell in vivo and in vitro, to explore the function and mechanism of its inhibition of mesangial cell activation, maintaining the steady-state and controlling mesangial damage in the initial stage of inflammation and to provide the new effective early intervention measures to mesangial proliferative glomerulonephritis.

系膜增生性肾炎是尿毒症的主要病因，多数研究聚焦在系膜细胞增殖和硬化的下游阶段。本项目在我们前一个国家自然科学基金重点项目的基础上，将研究的窗口前移，重点聚焦在抗Thy1抗体和IgA免疫复合物等致病因素如何激活系膜细胞、启动免疫炎症反应的上游阶段，揭示系膜细胞活化的关键分子、表型变化及分子标志、系膜细胞活化后的生物学效应、系膜细胞与内皮细胞及免疫细胞交叉对话对系膜免疫炎症的影响；发现并澄清激活系膜细胞的关键分子及信号通路；将细胞和动物实验获得的系膜细胞活化的标志物在人体系膜增生性IgA肾病患者标本中验证；提出“活化的系膜细胞是一种特殊的免疫炎症细胞”的学术观点。采用能发育为系膜细胞的Foxd1阳性的胚肾间充质细胞作为肾脏干（祖）细胞进行体内外干预实验，探讨其抑制系膜细胞活化、维持系膜细胞稳态、将系膜损伤阻抑在免疫炎症初始阶段的作用及分子机制，为系膜增生性肾炎提供新的早期干预的有效措施。

系膜增生性肾炎（mesangial proliferative glomerulonephritis，MsGN）是一种免疫炎症相关性疾病，是我国慢性肾脏病最常见的病因，系膜细胞积极参与肾脏局部的炎症反应，起着重要的调节作用，但机理至今尚未阐明。本项目重点聚焦抗 Thy-1抗体等致病因素激活系膜细胞、启动免疫炎症反应的分子机制，系膜细胞活化后的生物学效应，系膜细胞和免疫细胞的交叉对话对免疫炎症的影响，及采用能发育为系膜细胞的Foxd1+的后肾间充质细胞作为肾脏干/祖细胞进行体内外干预实验，探讨其抑制系膜细胞活化、维持系膜细胞稳态、将系膜损伤阻抑在免疫炎症初始阶段的作用机制。通过建立抗 Thy-1肾炎大鼠模型明确单核巨噬细胞以及T淋巴细胞在模型大鼠肾小球内沉积规律；通过单核巨噬细胞、T淋巴细胞与系膜细胞共培养，证实活化的系膜细胞能够摄取以及处理提呈抗，在炎症状态下扮演非专职抗原提呈细胞的角色，是一种特殊的免疫细胞，提出并证实“系膜活化”的概念；利用基因芯片、CHIP-SEQ以及荧光素酶实验揭示系膜细胞与单核巨噬细胞相互作用机制：活化的系膜细胞通过DBP-Trim55通路调控CCL2表达，趋化单核巨噬细胞，影响巨噬细胞极化，参与MsGN的发生发展；发现并证实SOCS1/STAT1可以调节系膜细胞抗原提呈分子标志物 MHC class II 和相关细胞因子的表达，影响CD4+T 淋巴细胞增殖与浸润；系膜细胞与免疫细胞协同作用，形成免疫炎症的瀑布反应，致使免疫炎症加剧和系膜细胞增殖；发现并证实Foxd1+后肾间充质细胞能够通过多种途径促进肾小球系膜损伤修复、稳定系膜正常结构和功能，为寻找系膜增生性肾炎新的早期干预的有效措施提供基础。