Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli
Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli
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DOI：
10.1172/jci200419139
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发表时间：
2004-06-01
影响因子：
15.9
通讯作者：
Winchester, RJ
中科院分区：
文献类型：
--
作者：
Peterson, KS;Huang, JF;Winchester, RJ
应用基因芯片技术分析临床活检肾小球组织中的基因表达，探讨局灶性/弥漫性增生性狼疮性肾炎的分子发病机制。通过激光捕获显微镜分离的肾小球的转录表型显示相当大的肾-肾异质性增加的转录表达，导致四个主要的基因簇，确定存在的B细胞，几个骨髓单核细胞谱系，成纤维细胞和上皮细胞增殖，基质改变，和I型IFN诱导基因的表达。肾内肾小球间变异不明显。髓系转录物，在分离的活化的巨噬细胞和髓系树突状细胞中发现的特征，广泛分布在所有活检样本。一个主要的样本亚组表达了与肾小球硬化病理学证据相关的纤维化相关基因;然而，TGF-β 1表达减少反对其在狼疮肾纤维化中的作用。第二组样本I型IFN诱导型转录物的表达与纤维化相关基因表达减少和病理特征较轻相关。这种基因表达模式类似于活化的NK细胞所表现出的。在所有样本中发现一个表达降低的大基因簇，包括离子通道和转录因子，表明对肾小球损伤的功能丧失反应。
The molecular pathogenesis of focal/diffuse proliferative lupus glomerulonephritis was studied by cDNA microarray analysis of gene expression in glomeruli from clinical biopsies. Transcriptional phenotyping of glomeruli isolated by laser-capture microscopy revealed considerable kidney-to-kidney heterogeneity in increased transcript expression, resulting in four main gene clusters that identified the presence of B cells, several myelomonocytic lineages, fibroblast and epithelial cell proliferation, matrix alterations, and expression of type I IFN-inducible genes. Glomerulus-to-glomerulus variation within a kidney was less marked. The myeloid lineage transcripts, characteristic of those found in isolated activated macrophages and myeloid dendritic cells, were widely distributed in all biopsy samples. One major subgroup of the samples expressed fibrosis-related genes that correlated with pathological evidence of glomerulosclerosis; however, decreased expression of TGF-beta1 argued against its role in lupus renal fibrosis. Expression of type I IFN-inducible transcripts by a second subset of samples was associated with reduced expression of fibrosis-related genes and milder pathological features. This pattern of gene expression resembled that exhibited by activated NK cells. A large gene cluster with decreased expression found in all samples included ion channels and transcription factors, indicating a loss-of-function response to the glomerular injury.