Genetic susceptibility to experimental autoimmune glomerulonephritis in the Wistar Kyoto rat

John Reynolds, Paul R Cook, Jacques Behmoaras, Jennifer Smith, Gurjeet Bhangal, Susan Tadros, Jonathan Tee, Alan D Salama, David J Evans, Timothy J Aitman, H Terence Cook, Charles D Pusey

Research output: Contribution to journalArticlepeer-review

Abstract

In experimental autoimmune glomerulonephritis (EAG), a model of Goodpasture's disease, Wistar Kyoto (WKY) rats immunized with collagenase-solubilized glomerular basement membrane (GBM) or the recombinant NC1 domain of the α3 chain of type IV collagen [α3(IV)NC1] develop anti-GBM antibodies and focal necrotizing glomerulonephritis with crescent formation. However, Lewis (LEW) rats, which share the same major histocompatibility complex (MHC) haplotype, are resistant to EAG development. A genome-wide linkage analysis of backcrossed animals with EAG revealed a major quantitative trait locus (QTL) on rat chromosome 13 (LOD = 3.9) linked to the percentage of glomerular crescents. To investigate the role of this QTL in EAG induction, reciprocal congenic rats were generated (LEW.WCrgn1 congenic and WKY.LCrgn1 congenic), immunized with recombinant rat α3(IV)NC1, and assessed for EAG development. WKY.LCrgn1 rats showed a marked reduction in albuminuria, severity of crescentic nephritis, and number of glomerular macrophages compared with WKY controls. No reduction in antibody levels was observed. However, LEW.WCrgn1 rats were resistant to EAG development, as were LEW controls. Macrophage activation in vitro was assessed in parental and congenic rat bone marrow-derived macrophages (BMDMs). WKY.LCrgn1 BMDMs showed a significant reduction in Fc receptor-mediated oxidative burst, phagocytosis of opsonised polystyrene beads, and LPS-induced levels of MCP-1 secretion and iNOS mRNA expression compared with WKY rats. These results confirm the importance of Crgn1 on chromosome 13 in EAG susceptibility, mediated partly through differences in Fc receptor-mediated macrophage activation.

Original languageEnglish
Pages (from-to)1843-51
Number of pages9
JournalAmerican Journal of Pathology
Volume180
Issue number5
DOIs
Publication statusPublished - May 2012

Keywords

  • Animals
  • Animals, Congenic
  • Anti-Glomerular Basement Membrane Disease
  • Autoantibodies
  • Autoantigens
  • Chemokine CCL2
  • Collagen Type IV
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Glomerular Basement Membrane
  • Kidney Glomerulus
  • Macrophage Activation
  • Macrophages
  • Male
  • Nitric Oxide Synthase Type II
  • Phagocytosis
  • Phenotype
  • Quantitative Trait Loci
  • Rats
  • Rats, Inbred Lew
  • Rats, Inbred WKY
  • Receptors, Fc
  • Recombinant Proteins
  • Respiratory Burst
  • Species Specificity

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