1. Am J Pathol. 2012 May;180(5):1843-51. doi: 10.1016/j.ajpath.2012.01.029. Epub
2012 Mar 22.
Genetic susceptibility to experimental autoimmune glomerulonephritis in the
Wistar Kyoto rat.
Reynolds J(1), Cook PR, Behmoaras J, Smith J, Bhangal G, Tadros S, Tee J, Salama
AD, Evans DJ, Aitman TJ, Cook HT, Pusey CD.
Author information:
(1)Renal Section, Department of Medicine, Imperial College London, Hammersmith
Campus, London, United Kingdom. john.reynolds@imperial.ac.uk
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.
Copyright © 2012 American Society for Investigative Pathology. Published by
Elsevier Inc. All rights reserved.
PMCID: PMC3532591
PMID: 22445570 [PubMed - indexed for MEDLINE]
PUBMED: 22445570
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