Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function.
Identification of Ceruloplasmin as a Gene that Affects Susceptibility to Glomerulonephritis Through Macrophage Function.
复制标题
DOI：
10.1534/genetics.116.197376
复制
发表时间：
2017-06
期刊：
影响因子：
3.3
通讯作者：
Behmoaras J
中科院分区：
文献类型：
--
作者：
Chen TD;Rotival M;Chiu LY;Bagnati M;Ko JH;Srivastava PK;Petretto E;Pusey CD;Lai PC;Aitman TJ;Cook HT;Behmoaras J
新月体肾小球肾炎 (Crgn) 是一种复杂的疾病，其中巨噬细胞活性和浸润是重要的效应原因。在之前使用独特易感 Wistar京都 (WKY) 大鼠品系的连锁研究中，我们鉴定了多个新月体肾小球肾炎 QTL (Crgn) 和 Crgn1 和 Crgn2 的位置克隆基因，这些基因占肾小球炎症总变异的 40%。在这里，我们生成了一个回交 (BC) 群体 (n = 166)，其中 Crgn1 和 Crgn2 被遗传固定，并发现与 2 号染色体上的肾小球新月体 (Crgn8，LOD = 3.8) 存在显着连锁。通过与来自同一 BC 群体的全基因组表达 QTL (eQTL) 整合进行精细作图分析，将铜蓝蛋白 (Cp) 确定为巨噬细胞中的位置 eQTL，但在血清中则不然。液相色谱-串联质谱法证实 Cp 是大鼠巨噬细胞中的蛋白质 QTL。 WKY 巨噬细胞过度表达 Cp，并且 RNA 干扰对其下调会降低肾小球促炎巨噬细胞激活的标志物。同样，与 Cp 短暂孵育会导致大鼠中应变依赖性巨噬细胞极化。这些结果表明，基因决定的 Cp 水平可以通过巨噬细胞功能改变对 Crgn 的敏感性，并提出 Cp 在早期巨噬细胞激活中的新作用。
Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.