血浆型gelsolin（pGSN）在IgA肾病肾小球纤维化中的作用及机制

IgA nephropathy（IgAN） is the most common form of progressive primary glomerulonephritis worldwide，the disease leads to end stage renal disease (ESRD) due to renal fibrosis in a substantial proportion of patients in more than ten years, therefore renal fibrosis plays an important role in the progress of IgAN, The mechanisms underlying renal fibrosis in IgAN remained unclear. In the preliminary experiments, we found that the plasma gelsolin (pGSN) in serum obviously decreased, the pGSN content in renal tissue increased significantly with positive correlation with TGF- β 1 and glomerular fibrosis degree in IgAN, the result was confirmed by the experimental animal models of IgAN and expression profiles after pGSN adminstration in mesangial cells, it suggests that pGSN may be involved in glomerular fibrosis in IgAN. The relationship between pGSN and glomerular fibrosis in IgAN has not reported now. Multiple levels including serum, renal tissue in patients and primary cultured mesangial cell, immunology and molecular biology in our research will be utilized to elucidate the role and molecular mechanism of pGSN in glomerular fibrosis in IgAN，whereby providing important experimental basis for the choice of medication time and judgement progrosis. This study has important scientific significance and potential application value.

IgAN是全世界常见的原发性肾小球肾炎之一，部分患者因肾纤维化10余年进展为终末性肾病，因此肾纤维化在IgAN进展占有重要地位，但是IgAN的肾纤维化的确切机制现在还不清楚。本课题组在前期预实验中发现IgAN患者血清血浆型gelsolin（plasma gelsolin,pGSN）下降最为明显，肾小球中pGSN含量明显增加且与TGF-β1和肾小球纤维化程度呈正相关，IgAN患者的这些结果在IgAN动物模型和pGSN处理系膜细胞后的表达谱的预实验中得到证实，由此推测pGSN可能参与IgAN肾小球的纤维化。pGSN和IgAN肾小球纤维化的关系，迄今国内外未见报道。本研究通过患者血清、肾组织及原代培养的系膜细胞，采用免疫学和分子生物学等手段探讨pGSN在IgAN肾小球纤维化的作用，明确其致纤维化机制，为选择药物治疗时机和预后预判奠定重要的实验基础。本研究具有重要的科学意义和潜在的应用价值。

目的：血浆型gelsolin (pGSN)是一种actin结合蛋白，其在类风湿性关节炎中发挥重要的作用。然而，pGSN是否参与其他类型的免疫性疾病的发生并不清楚。pGSN和IgAN的关系是本研究研究的重点。.方法：选取IgAN、其他类型的肾病和正常人各200例，这些标本来自于2000年到2014年的肾活检组织。牛津分类系统用来评估疾病进展的风险。检测血清和肾组织的pGSN，并分析pGSN与IgA、半乳糖缺陷IgA1、转化生长因子β1、纤连蛋白、临床症状和肾功能的相关性。验证其影响系膜细胞的的信号途径。.结论：IgAN 患者血清pGSN 水平明显低于其他类型的肾病和正常人。血清中pGSN 与血清中IgA1, FN, and TGF-β1 水平呈负相关关系，与肾小球滤过率呈正相关关系。相反，肾小球内的pGSN 在肾小球内沉积明显增多，且与肾小球内FN和 TGF-β1水平呈正相关关系。在牛津分类 M1和 S1的肾小球内沉积明显高于M0和 S0 (p < 0.05)。与此同时， pGSN通过促进有丝分裂促进人系膜增殖。pGSN促进系膜细胞表达整合素α2β1，并且通过 integrin α2β1-pGSN结合而发挥作用。pGSN通过p38-MAPK途径促进细胞的增殖。.结论：本研究发现 pGSN通过促进系膜细胞增殖而在IgAN进展中发挥重要的作用，血清和肾小球内的pGSN可能是预测 IgAN 预后和进展的重要指标。体外实验证实pGSN通过p38-MAPK途径促进系膜细胞的增殖。