RRC ID 4357
Author Behmoaras J, Bhangal G, Smith J, McDonald K, Mutch B, Lai PC, Domin J, Game L, Salama A, Foxwell BM, Pusey CD, Cook HT, Aitman TJ.
Title Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility.
Journal Nat Genet
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) 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.
Volume 40(5)
Pages 553-9
Published 2008-5
DOI 10.1038/ng.137
PII ng.137
PMID 18443593
PMC PMC2742200
MeSH Animals Animals, Congenic Chromosome Mapping Gene Expression Genetic Linkage Genetic Predisposition to Disease* Glomerulonephritis / genetics* Haplotypes Humans Macrophage Activation / genetics* Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism Proto-Oncogene Proteins c-jun / physiology* Rats / genetics* Rats, Inbred Lew Rats, Inbred WKY Transcription Factor AP-1 / genetics Transcription Factor AP-1 / metabolism Transcription Factor AP-1 / physiology*
IF 25.455
Times Cited 63
WOS Category GENETICS & HEREDITY
Resource
Rats WTC/Kyo(strainID=18) WKYO/Kyo(strainID=17) DON/Kyo(strainID=1) IS/KYO(strainID=25)