| 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 |
2008-5-1
|
| 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 |
27.605
|
| 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) |
