Genome-Wide Analysis of Genes Related to Kidney Stone Formation and Elimination in the Calcium Oxalate Nephrolithiasis Model Mouse: Detection of Stone-Preventive Factors and Involvement of Macrophage Activity
Genome-Wide Analysis of Genes Related to Kidney Stone Formation and Elimination in the Calcium Oxalate Nephrolithiasis Model Mouse: Detection of Stone-Preventive Factors and Involvement of Macrophage Activity
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DOI：
10.1359/jbmr.081245
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发表时间：
2009-05-01
影响因子：
6.2
通讯作者：
Kohri, Kenjiro
中科院分区：
文献类型：
--
作者：
Okada, Atsushi;Yasui, Takahiro;Kohri, Kenjiro
我们之前建立了小鼠肾结石形成模型，并表明小鼠比大鼠对结石形成有更高的耐受性。此外，我们还表明，生成的草酸钙晶体沉淀物可以在几天后消除。本研究利用基因芯片技术，基于基因选择，研究了小鼠肾脏结石形成和排出的转录组。给8周龄雄性C57BL/6N小鼠灌胃80 mg/kg乙醛15天后，肾脏草酸钙晶体沉积增加，此后逐渐减少，至15天基本消失。基因芯片分析显示，晶体形成的肾脏中有18,064个基因的显著表达。31个、21个和25个基因分别在实验过程(第3-15天)、结石形成阶段(第3-6天)和结石清除阶段(第9-15天)至少增加了2倍的表达。在这些基因中，发现了与趋化和单核/巨噬细胞激活相关的基因。基因本体论分析识别高表达的基因，突出与炎症、免疫反应和补体激活途径相关的类别。对已报道的17个在芯片上有显著表达的结石相关基因进行定量聚合酶链式反应，结果显示，在整个实验过程中，趋化因子、结石基质蛋白及其受体显著增加，几种转运蛋白和超氧化物歧化酶显著降低，Tamm-Horsfall蛋白持续高表达。总之，巨噬细胞迁移引起的炎症和免疫反应参与了小鼠肾脏结石的形成和排出。
We previously established a mouse kidney stone formation model and showed that mice have a higher tolerance to stone formation than rats. Furthermore, we showed that the generated calcium oxalate crystal deposits could be eliminated after several days. This study investigated the transcriptome of stone formation and elimination in the mouse kidney based on gene selection using a microarray technique. Eight-week-old male C57BL/6N mice were administered 80 mg/kg glyoxylate for 15 days, and kidney calcium oxalate crystal depositions had increased by day 6; thereafter, depositions decreased gradually and had almost disappeared by day 15. On microarray analysis, mRNA expression in the crystal-formed kidneys showed the significant expression of 18,064 genes. Thirty-one, 21, and 25 genes showed at least a 2-fold increased expression during the experimental course (days 3-15), stone formation phase-specific (days 3-6), and stone elimination phase-specific (days 9-15) stages, respectively. Among these genes, those related to chemotaxis and monocyte/macrophage activation were identified. Gene ontology analysis to identify overexpressed genes highlighted categories related to inflammation, immune reactions and the complement activation pathway. Quantitative PCR of 17 previously reported stone-related genes with a significant expression on microarray analysis showed significantly increased chemokines, stone matrix proteins, and their receptors; the significant decrease of several types of transporters and superoxide dismutase; and the persistently high expression of Tamm-Horsfall protein throughout the experiment. In conclusion, inflammation and immune reactivity through macrophage migration are involved in stone formation and elimination in mouse kidneys.