原发性局灶节段性肾小球硬化症中可溶性尿激酶受体的致病性片段的研究

Focal segmental glomerulosclerosis (FSGS) is an important cause of steroid-resistant nephrotic syndrome, its etiology has not been fully illuminated. It has been reported that soluble urokinase receptor (suPAR) might be the most likely pathogenic circulating permeability factor. In our preliminary study, we found that suPAR was specially elevated in primary FSGS, it could induce podocyte injury in primary FSGS through the activation of integrin αvβ3, which then completed the signal transmission. There were three forms of suPAR, the exact pathogenic fragment was still unknown. In this study, we aimed to look for the pathogenic forms of suPAR in primary FSGS patients by immunoprecipitation and mass spectrometry. We would observe whether this fragment induced podocyte injury, including the change of the structure and function, though transwell migration assay, would healing assay and some other testing methods. We would also observe the damage of kidney and podocyte in pathogenic suPAR fragments induced nephropathy animal models and its damage mechanism. This study would illuminate one of the etiology of primary FSGS and be meaningful in providing new directions for the diagnosis and treatment of this disease.

原发性局灶节段性肾小球硬化症(FSGS)是激素抵抗型肾病综合征的主要类型之一，其发病机制未完全阐明。可溶性尿激酶受体（suPAR）很可能是原发性FSGS的一个重要的循环致病因子。我们前期工作发现suPAR在原发性FSGS中具有较高的疾病特异性，可以通过活化人类足细胞上的整合素β3引起足细胞损伤，参与致病。但suPAR有3中不同的形式，其具体致病性片段尚未阐明。本研究拟通过免疫沉淀及质谱分析的方法寻找原发性FSGS的致病性suPAR片段，并通过体外细胞实验和动物实验，综合利用transwell实验、损伤-修复实验等及多种干预和检测手段，探讨该致病片段对足细胞结构、功能的影响及其作用机制，以助于阐明原发性FSGS发病机制（之一），为该病的诊断及治疗提供新的线索。

原发性局灶节段性肾小球硬化症(FSGS)是激素抵抗型肾病综合征的主要类型之一，其发病机制未完全阐明。我们前期工作发现suPAR在原发性FSGS中较正常人显著升高。suPAR有3种不同的形式，我们通过免疫共沉淀方法提取患者与正常人的所有suPAR片段，蛋白电泳结果提示FSGS患者与正常人之间有不同的蛋白条带，可能为致病性片段。同时我们发现原发性FSGS患者肾组织IgM和C3的沉积与治疗反应和肾脏预后相关。通过ELISA方法检测原发性FSGS患者血浆及尿液中补体谱（C3a, C5a, soluble C5b-9, C4d, C1q, MBL, and Bb）, 结果提示FSGS患者体内确实存在系统性的补体活化，其可能通过经典途径及旁路途径激活补体。补体的活化程度与该病的临床表现、肾脏病理损伤及肾脏预后密切相关，这提示补体系统活化可能参与了该病的发病。