Analysis of onset mechanism in refractory glomerulonephritis with DNA microanray

DNA显微分析难治性肾小球肾炎发病机制

基本信息

批准号：
13671104
负责人：
UENO Mitsuhiro
金额：
$ 2.18万
依托单位：
Niigata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Both IgA nephropathy and crescentic glomerulonephritis are typical of refractory glomerulonephritis. The precise onset mechanisms of both glomerulonephtitis are unknown. However genetical factors may be associated with the onset of IgA nephropathy because of familial clustering. We attempted to investigate the possible role of various gene polymorphisms in IgA nephropathy and studied any possible associations between gene variation and the clinical manifestations, especially renal prognosis in about 250 patients. As a result, we demonstrated that single nucleotide polymorphisms of polymeric immunoglobulin receptor, uteroglobin, angiotensin converting enzyme angiotensinogen aldosterone synthase, SA, α addducin and peroxisome proliferator-activated receptor γ were related to renal prognosis of IgA nephropathy.Rat anti-glomerular basement membrane(GBM) nephritis is a model of crescentic glomerulonepnntis induced by the administration of anti-GBM antiserum. To elucidate the mechanism of gl … More omerular injury, we analyzed the gene expression patterns in the kidneys of anti-GBM nephritis rats using DNA arrays, and found that macropgage metalloelastase/matrix metalloproteinase(MMP)-12 was lone of the highly expressed genes in the kidneys on days 3 and 7 after the injection of anti-GBM antiserum. Enhancement of MMP-12 mRNA expression was confirmed by Northern blot analysis, and in situ hybridization revealed that MMP-12 mRNA was expressed in ED-1-positive macrophages and multinuclear giant cells in the glomeruli with crescent. Moreover, these cells were positive with anti-rat rMMP-12 Ab on the section of the kidneys of anti-GBM nephritis rats on day 7. To clarify the role of MMP-12, we conducted a neutralization experiment using anti-rat rMMP-12 Ab. Consequently, crescent formation and macrophage infiltration in the glomeruli were significantly rethiced in the rats treated with anti-rat rMMP-12 Ab, and the amount of urine protein was also decreased. These results disclosed that MMP-12 played an important role in glomerular injury in a crescentic glomerulonephritis model. Less

IgA肾病和新月肾小球肾炎都是难治性肾小球肾炎的典型特征。两种肾小球肾炎的精确发作机制尚不清楚。但是，由于家族性聚类，遗传因素可能与IgA肾病的发作有关。我们试图研究各种基因多态性在IgA肾病中的可能作用，并研究了基因变异与临床表现之间的任何可能关联，尤其是大约250名患者的肾脏预后。结果，我们证明了聚合物免疫球蛋白受体，子宫球蛋白，血管紧张素转化酶血管紧张素醛固酮合酶，SA，α添加剂和过氧化物体增生受体激活受体γ的单一核唯一多态性膜（GBM）肾炎是由抗GBM抗血清诱导的新年肾上腺肾小球酮的模型。为了阐明GL…更明确损伤的机制，我们使用DNA阵列分析了抗GBM肾炎大鼠肾脏中的基因表达模式，发现巨型偏金属赛/基质金属蛋白酶（MMP）-12是在第3和7天的注射中是高度表达的基因的单次，在第3和7天被注入。通过Northern印迹分析证实了MMP-12 mRNA表达的增强，原位杂交表明，MMP-12 mRNA在ED-1阳性巨噬细胞中表达，并在glomerulli中带有Crescent中的多核巨细胞。此外，这些细胞在第7天的抗GBM肾炎大鼠肾脏的肾小管部分呈阳性。为了阐明MMP-12的作用，我们使用抗RAT RMMP-12 AB进行了谈判实验。因此，肾小球中的新月形形成和巨噬细胞浸润在用抗rat RMMP-12 AB处理的大鼠中显着重新定性，并改善了尿液蛋白的量。这些结果表明，在新月肾小球肾炎模型中，MMP-12在肾小球损伤中起着重要作用。较少的