Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility.
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.
Behmoaras
Jacques
J
Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
Bhangal
Gurjeet
G
Smith
Jennifer
J
McDonald
Kylie
K
Mutch
Brenda
B
Lai
Ping Chin
PC
Domin
Jan
J
Game
Laurence
L
Salama
Alan
A
Foxwell
Brian M
BM
Pusey
Charles D
CD
Cook
H Terence
HT
Aitman
Timothy J
TJ
D000818:Animals; D020296:Animals, Congenic; D002874:Chromosome Mapping; D015870:Gene Expression; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008262:Macrophage Activation / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats / Q000235:genetics*; D011917:Rats, Inbred Lew; D011921:Rats, Inbred WKY; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1