Gene expression profiling of anti-GBM glomerulonephritis model:: The role of NF-κB in immune complex kidney disease
Gene expression profiling of anti-GBM glomerulonephritis model:: The role of NF-κB in immune complex kidney disease
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DOI：
10.1111/j.1523-1755.2004.00956.x
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发表时间：
2004-11-01
影响因子：
19.6
通讯作者：
Park, WY
中科院分区：
文献类型：
--
作者：
Kim, JH;Ha, IS;Park, WY
背景免疫复合物可能导致慢性肾脏疾病的不可逆发作。大多数慢性肾脏疾病患者经历最终共同途径，以肾小球硬化和间质纤维化为标志。我们尝试用寡核苷酸芯片技术绘制小鼠抗肾小球基底膜（GBM）肾炎的分子图谱。在使用抗GBM抗体诱导肾小球肾炎后的第1、3、7、11和16天收获肾脏。在检查生物化学和组织学变化的同时，针对5个合并的对照肾获得基因表达谱。基因表达水平通过逆转录-聚合酶链反应（RT-PCR）、实时PCR或荧光化学交叉验证。在BALB/c和C57 BL/6株中证实了抗GBM肾小球肾炎的病理变化。在13，680个点样的65聚体寡核苷酸中，选择通过具有多重检验校正的排列方差分析（ANOVA）显示显著时间模式的1112个基因[错误发现率（FDR）< 0.05]用于聚类分析。从表达谱，急性炎症反应的特点是各种细胞因子，包括白细胞介素（IL）-1和IL-6的升高，在疾病发作的3天内确定。7天后，组织重塑反应是突出的高度诱导的细胞外基质（ECM）基因。虽然未检测到与淋巴细胞活化相关的细胞因子，但单核细胞或系膜细胞增殖相关基因增加。肿瘤坏死因子-α（TNF-α）和核因子-κ B（NF-κ B B）通路在整个疾病进展过程中持续激活，诱导多种靶基因如补体3、IL-1 B、IL-6、Traf 1和Saa 1的表达。我们制作了一个大规模的小鼠抗GBM肾小球肾炎模型的基因表达时间表，为炎症性肾脏疾病的发生和发展机制提供了一个全面的概述。
Background. Immune complexes may cause an irreversible onset of chronic renal disease. Most patients with chronic renal disease undergo a final common pathway, marked by glomerulosclerosis and interstitial fibrosis. We attempted to draw a molecular map of anti-glomerular basement membrane (GBM) glomerulonephritis in mice using oligonucleotide microarray technology.Methods. Kidneys were harvested at days 1, 3, 7, 11, and 16 after inducing glomerulonephritis by using anti-GBM antibody. In parallel with examining the biochemical and histologic changes, gene expression profiles were acquired against five pooled control kidneys. Gene expression levels were cross-validated by either reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR, or immunohistochemistry.Results. Pathologic changes in anti-GBM glomerulonephritis were confirmed in both BALB/c and C57BL/6 strains. Among the 13,680 spotted 65mer oligonucleotides, 1112 genes showing significant temporal patterns by permutation analysis of variance (ANOVA) with multiple testing correction [false discovery ratio (FDR) < 0.05] were chosen for cluster analysis. From the expression profile, acute inflammatory reactions characterized by the elevation of various cytokines, including interleukin (IL)-1 and IL-6, were identified within 3 days of disease onset. After 7 days, tissue remodeling response was prominent with highly induced extracellular-matrix (ECM) genes. Although cytokines related to lymphocyte activation were not detected, monocyte or mesangial cell proliferation-related genes were increased. Tumor necrosis factor-alpha (TNF-alpha) and nuclear factor-kappa B (NF-kappa B) pathway were consistently activated along the entire disease progression, inducing various target genes like complement 3, IL-1b, IL-6, Traf1, and Saa1.Conclusion. We made a large-scale gene expression time table for mouse anti-GBM glomerulonephritis model, providing a comprehensive overview on the mechanism governing the initiation and the progression of inflammatory renal disease.