Microarray analysis of glomerular gene expression in murine lupus nephritis
Microarray analysis of glomerular gene expression in murine lupus nephritis
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DOI：
10.1254/jphs.fp0071337
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发表时间：
2008-01-01
影响因子：
3.5
通讯作者：
Miura, Katsuyuki
中科院分区：
文献类型：
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作者：
Teramoto, Kae;Negoro, Nobuo;Miura, Katsuyuki
为了阐明狼疮性肾炎肾小球事件的分子机制，我们对狼疮性肾炎小鼠肾小球进行了全基因组的mRNA表达分析。给12周龄MRL/LPR小鼠灌胃赋形剂或强的松龙(10 mg/kg/d)，连续4周。MRL/LPR小鼠的肾脏组织学显示系膜增生性肾小球肾炎伴有巨噬细胞、T细胞和中性粒细胞的细胞渗透。我们在MRL/LPR肾小球中发现了567个上调基因，与对照的同源基因小鼠相比。这些包括补体成分、黏附分子、趋化因子及其受体，以及与抗原提呈相关的分子。超过130个基因被认为在造血细胞谱系中优先或唯一表达，可能反映了白细胞的聚集。值得注意的是，与T辅助1(Th1)细胞聚集相关的趋化因子和趋化因子受体(CCL3、CCL4、CCL5、CXCL9、CXCL10、CXCL11、CXCL16、CCR5、CXCR3和CXCR6)随着IL-27亚单位Ebi3表达的上调而上调，Ebi3是IL-27的一个亚单位，在Th1占优势地位。伴随这些变化的是Th1细胞因子干扰素-γ诱导的许多基因的mRNA表达增加。强的松龙明显减轻肾小球病变和白细胞内流，同时减少增强的基因表达。本研究显示了支持肾小球Th1细胞聚集及其作用的更多证据。我们的数据也为寻找狼疮性肾炎的新治疗靶点提供了重要的资源。
To elucidate the molecular mechanism of glomerular events in lupus nephritis, we performed genome-wide mRNA expression analysis of glomeruli microdissected from lupus mice. MRL/lpr mice (12-week-old) were orally given vehicle or prednisolone (10 mg/kg per day) for 4 weeks. Renal histology of MRL/lpr mice revealed mesangial proliferative glomerulonephritis with cellular infiltration of macrophages, T cells, and neutrophils. We identified 567 up-regulated genes in MRL/lpr glomeruli compared to control congenic mice. Those included complement components, adhesion molecules, chemokines and their receptors, and molecules related to antigen presentation. Over 130 genes were considered preferentially or exclusively expressed in hematopoietic cell lineages possibly reflecting leukocytes accumulation. Of note is the finding that chemokines and chemokine receptors (CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL 11, CXCL 16, CCR5, CXCR3, and CXCR6) that are related to T helper 1 (Th1) cells accumulation were up-regulated concomitantly with increased expression of Ebi3, a subunit of IL-27 that plays a role in Th1 predominance. These changes were accompanied by increased mRNA expression of many genes that were inducible by Th1 cytokine interferon-gamma. Prednisolone markedly attenuated glomerular lesion and leukocyte influx parallel with the reduction of enhanced gene expression. The present study shows additional evidence supporting glomerular Th1 cells accumulation and their role. Our data also provide an important resource in seeking new therapeutic targets to lupus nephritis.