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Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility

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  • Jacques Behmoaras
  • Gurjeet Bhangal
  • Jennifer Smith
  • Kylie McDonald
  • Brenda Mutch
  • Ping Chin Lai
  • Jan Domin
  • Laurence Game
  • Alan Salama
  • Brian M Foxwell
  • Charles D Pusey
  • H Terence Cook
  • Timothy J Aitman

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    Rights statement: Published in final edited form as: Nat Genet. May 2008; 40(5): 553–559.

    Accepted author manuscript, 1.16 MB, PDF document

http://www.nature.com/ng/journal/v40/n5/full/ng.137.html
Original languageEnglish
Pages (from-to)553-9
Number of pages7
JournalNature Genetics
Volume40
Issue number5
DOIs
Publication statusPublished - May 2008

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.

    Research areas

  • Animals, Animals, Congenic, Chromosome Mapping, Gene Expression, Genetic Linkage, Genetic Predisposition to Disease, Glomerulonephritis, Haplotypes, Humans, Macrophage Activation, Proto-Oncogene Proteins c-jun, Rats, Rats, Inbred Lew, Rats, Inbred WKY, Transcription Factor AP-1

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