Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
1] Laboratory of Anatomy, Department of Biomedical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan [2] Section of Biological Safety Research, Chitose Laboratory, Japan Food Research Laboratories, Chitose, Japan.
Genes Immun. 2014 Apr-May;15(3):182-9. doi: 10.1038/gene.2014.4. Epub 2014 Jan 30.
The autoimmune-prone BXSB/MpJ-Yaa mouse is a model of membranous proliferative glomerulonephritis (MPGN). Severe MPGN has been reported only in male BXSB/MpJ-Yaa mice because of the Y-linked autoimmune accelerator (Yaa) locus. However, we show that female BXSB/MpJ mice develop age-related MPGN without Yaa. Female BXSB/MpJ mice clearly developed MPGN characterized by increased mesangial cells, thickening of the glomerular basement membrane (GBM), double contouring and spike formation of GBM with T-cell infiltrations and podocyte injuries corresponding with increased autoantibody production and albuminuria. Analysis of the renal levels of the Fc gamma receptor (Fcgr) and interferon-activated gene 200 (Ifi200) family genes, which are MPGN candidate genes localized to the telomeric region of chromosome 1 (Chr.1), showed that Fcgr2b levels decreased, whereas Fcgr3 and Ifi202b levels increased in female BXSB/MpJ mice compared with healthy C57BL/6 mice. Furthermore, in isolated glomeruli, microarray analysis revealed that Fcgr3, Fcgr4 and Ifi202b expression was higher in male BXSB/MpJ-Yaa mice than in male BXSB/MpJ mice. These findings indicate that the BXSB/MpJ-type genome causes age-related MPGN with significant contribution from the telomeric region of Chr.1, and Yaa enhances the expression of genes localizing to this locus, thereby leading to severe MPGN in male mice.
自身免疫倾向的 BXSB/MpJ-Yaa 小鼠是膜性增殖性肾小球肾炎 (MPGN) 的模型。由于 Y 连锁自身免疫加速（Yaa）基因座，仅在雄性 BXSB/MpJ-Yaa 小鼠中报道了严重的 MPGN。然而，我们表明，雌性 BXSB/MpJ 小鼠在没有 Yaa 的情况下会发生与年龄相关的 MPGN。雌性 BXSB/MpJ 小鼠明显发展为 MPGN，其特征为系膜细胞增多、肾小球基底膜（GBM）增厚、GBM 双轮廓和刺形成，伴有 T 细胞浸润和足细胞损伤，与自身抗体产生和白蛋白尿增加相对应。对位于染色体 1 端粒区的 MPGN 候选基因 Fcγ 受体（Fcgr）和干扰素激活基因 200（Ifi200）家族基因的肾脏水平进行分析，结果表明，与健康 C57BL/6 小鼠相比，雌性 BXSB/MpJ 小鼠的 Fcgr2b 水平降低，而 Fcgr3 和 Ifi202b 水平升高。此外，在分离的肾小球中，微阵列分析显示，与雄性 BXSB/MpJ 小鼠相比，雄性 BXSB/MpJ-Yaa 小鼠中 Fcgr3、Fcgr4 和 Ifi202b 的表达更高。这些发现表明，BXSB/MpJ 型基因组导致与年龄相关的 MPGN，其显著贡献来自 Chr.1 的端粒区，Yaa 增强了该基因座定位基因的表达，从而导致雄性小鼠发生严重的 MPGN。
