Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice.
Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice.
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DOI：
10.1002/art.38679
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Davidson A
中科院分区：
文献类型：
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作者：
Bethunaickan R;Berthier CC;Zhang W;Eksi R;Li HD;Guan Y;Kretzler M;Davidson A
通过转录组分析阐明狼疮性肾炎进展、缓解和复发过程中肾脏炎症的分子机制。在NZB/W F1和NZM2410小鼠的疾病过程中或缓解诱导后，每隔一段时间收获来自NZB/W F1和NZM2410小鼠的肾脏。从灌注肾的微阵列分析获得全基因组表达谱。选择的基因的真实的时间PCR分析用于验证微阵列数据。使用SAM进行组间比较，并使用奇异值分解和自组织映射对整个数据集进行无偏分析。在肾炎前肾脏中检测到肾脏分子谱的变化很少，但在蛋白尿发作时基因表达发生了显著变化，反映了炎症细胞浸润和补体激活。随后的基因表达变化主要影响线粒体功能障碍和代谢应激途径。内皮细胞活化、组织重塑和肾小管损伤是肾功能丧失的主要途径。缓解诱导逆转了大多数但不是所有的炎症变化，并且复发进展与炎症复发、线粒体功能障碍和代谢应激特征相关。免疫细胞浸润和激活与蛋白尿的发生有关，并可通过免疫抑制治疗逆转，但疾病进展与肾缺氧和代谢应激有关。因此，SLE肾炎的最佳治疗可能需要针对免疫和非免疫疾病机制。此外，分子标记物的大量子集与人类狼疮肾中表达的分子标记物的重叠表明了潜在的新生物标记物和治疗靶点。
To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission and relapse of nephritis in murine lupus models using transcriptome analysis. Kidneys from NZB/W F1 and NZM2410 mice were harvested at intervals during their disease course or after remission induction. Genome wide expression profiles were obtained from microarray analysis of perfused kidneys. Real time PCR analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire dataset using singular value decomposition and self-organizing map were performed. Few changes in the renal molecular profile were detected in pre-nephritic kidneys but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all of the inflammatory changes and progression towards relapse was associated with recurrence of inflammation, mitochondrial dysfunction and metabolic stress signatures. Immune cell infiltration and activation is associated with proteinuria onset and reverses with immunosuppressive therapy but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy of SLE nephritis may therefore need to target both immune and non-immune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in human lupus kidneys suggests potential new biomarkers and therapeutic targets.