Abstract
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.
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Acknowledgements
We thank P. Froguel, E. Petretto and S. Cook for criticism of the manuscript. We thank T. Serikawa and the National Bio Resource Project in Japan for providing the Japanese rat strains. We acknowledge intramural funding from the Clinical Sciences Centre and support from the FP6 EURATools (European Union contract number LSHG-CT-2005-019015), the UK Medical Research Council and the Wellcome Trust. H.T.C, C.D.P., A.S. and T.J.A. acknowledge support from the UK National Institute for Health Research's Biomedical Research Centre funding scheme.
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J.B., T.J.A., C.D.P. and H.T.C. designed this study, J.S. performed congenic strain breeding and phenotyping. P.C.L., J.D. and L.G. carried out microarray experiments. J.B., G.B. and A.S. optimized the Fc oxyBURST assay. J.B., G.B., K.M., B.M. and B.M.F. performed all other experiments. J.B., T.J.A and H.T.C. wrote the manuscript.
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Behmoaras, J., Bhangal, G., Smith, J. et al. Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility. Nat Genet 40, 553–559 (2008). https://doi.org/10.1038/ng.137
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DOI: https://doi.org/10.1038/ng.137
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