Letter abstract
Nature Genetics 40, 553 - 559 (2008)
Published online: 28 April 2008 | doi:10.1038/ng.137
Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility
Jacques Behmoaras1,2, Gurjeet Bhangal2, Jennifer Smith2, Kylie McDonald1, Brenda Mutch3, Ping Chin Lai4, Jan Domin2, Laurence Game5, Alan Salama2, Brian M Foxwell3, Charles D Pusey2, H Terence Cook6,8 & Timothy J Aitman1,7,8
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) rat1. 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.
- Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- Renal Medicine; Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College of Science, Technology and Medicine, 1 Aspenlea Road, Hammersmith, London, W6 8LH, UK.
- Kidney Institute, Department of Nephrology, School of Medicine, Chang Gung University, Chang Gung Memorial Hospital, Taipei, Taiwan.
- Clinical Science Centre–Imperial College Microarray Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- Department of Histopathology, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- Section of Molecular Genetics and Rheumatology, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- These authors contributed equally to this work.
Correspondence to: Timothy J Aitman1,7,8 e-mail: t.aitman@imperial.ac.uk
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