Behmoaras Jacques, Bhangal Gurjeet, Smith Jennifer, McDonald Kylie, Mutch Brenda, Lai Ping Chin, Domin Jan, Game Laurence, Salama Alan, Foxwell Brian M, Pusey Charles D, Cook H Terence, Aitman Timothy J
Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
Nat Genet. 2008 May;40(5):553-9. doi: 10.1038/ng.137.
Crescentic glomerulonephritis is an important cause of human kidney failure for which the underlying molecular basis is largely unknown. In previous studies, we mapped several susceptibility loci, Crgn1-Crgn7, for crescentic glomerulonephritis in the Wistar Kyoto (WKY) rat. Here we show by combined congenic, linkage and microarray studies that the activator protein-1 (AP-1) transcription factor JunD is a major determinant of macrophage activity and is associated with glomerulonephritis susceptibility. Introgression of Crgn2 from the nonsusceptible Lewis strain onto the WKY background leads to significant reductions in crescent formation, macrophage infiltration, Fc receptor-mediated macrophage activation and cytokine production. Haplotype analysis restricted the Crgn2 linkage interval to a 430-kb interval containing Jund, which is markedly overexpressed in WKY macrophages and glomeruli. Jund knockdown in rat and human primary macrophages led to significantly reduced macrophage activity and cytokine secretion, indicating conservation of JunD function in macrophage activation in rats and humans and suggesting in vivo inhibition of Jund as a possible new therapeutic strategy for diseases characterized by inflammation and macrophage activation.
新月体性肾小球肾炎是导致人类肾衰竭的一个重要原因，其潜在的分子基础在很大程度上尚不清楚。在先前的研究中，我们在Wistar京都（WKY）大鼠中定位了几个新月体性肾小球肾炎的易感基因座Crgn1 - Crgn7。在此，我们通过基因共导入、连锁分析和微阵列研究表明，激活蛋白-1（AP-1）转录因子JunD是巨噬细胞活性的主要决定因素，并且与肾小球肾炎易感性相关。将非易感的刘易斯品系的Crgn2导入WKY背景中，可导致新月体形成、巨噬细胞浸润、Fc受体介导的巨噬细胞激活和细胞因子产生显著减少。单倍型分析将Crgn2的连锁区间限定在一个包含Jund的430 kb区间内，Jund在WKY巨噬细胞和肾小球中明显过表达。在大鼠和人类原代巨噬细胞中敲低Jund导致巨噬细胞活性和细胞因子分泌显著降低，这表明JunD在大鼠和人类巨噬细胞激活中的功能具有保守性，并提示体内抑制Jund可能是治疗以炎症和巨噬细胞激活为特征的疾病的一种新的治疗策略。
