RGD Reference Report - Genetic Loci Modulate Macrophage Activity and Glomerular Damage in Experimental Glomerulonephritis. - Rat Genome Database

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Genetic Loci Modulate Macrophage Activity and Glomerular Damage in Experimental Glomerulonephritis.

Authors: Behmoaras, J  Smith, J  D'Souza, Z  Bhangal, G  Chawanasuntoropoj, R  Tam, FW  Pusey, CD  Aitman, TJ  Cook, HT 
Citation: Behmoaras J, etal., J Am Soc Nephrol. 2010 May 20.
RGD ID: 2325762
Pubmed: PMID:20488952   (View Abstract at PubMed)
PMCID: PMC3152224   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2009090968   (Journal Full-text)

The Wistar Kyoto (WKY) rat is uniquely susceptible to experimentally induced crescentic glomerulonephritis. Two major quantitative trait loci (QTLs) on chromosomes 13 (Crgn1) and 16 (Crgn2) with logarithm of odds >8, as well as five other loci (Crgn3 through 7), largely explain this genetic susceptibility. To understand further the effects of Crgn1 and Crgn2, we generated a double-congenic strain by introgressing these loci from glomerulonephritis-resistant Lewis rats onto the WKY genetic background. Induction of nephrotoxic nephritis in the double-congenic rats (WKY.LCrgn1,2) produced markedly fewer glomerular crescents, reduced macrophage infiltration, and decreased expression of glomerular TNF-alpha and inducible nitric oxide synthase expression compared with control animals. Bone marrow and kidney transplantation studies between parental and WKY.LCrgn1,2 strains, together with in vitro experiments, demonstrated that Crgn1 and Crgn2 contribute exclusively to circulating cell-related glomerular injury by regulating macrophage infiltration and activation. The residual genetic susceptibility to crescentic glomerulonephritis in WKY.LCrgn1,2 rats associated with macrophage activity (especially with enhanced metalloelastase expression) rather than macrophage infiltration. Taken together, these results demonstrate that a genetic influence on macrophage activation, rather than number, determines glomerular damage in immune-mediated glomerulonephritis.



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Mammalian Phenotype

Objects Annotated

Genes (Rattus norvegicus)
Mmp12  (matrix metallopeptidase 12)

Genes (Mus musculus)
Mmp12  (matrix metallopeptidase 12)

Genes (Homo sapiens)
MMP12  (matrix metallopeptidase 12)

Objects referenced in this article
QTL Glom15 Glomerulus QTL 15 Rattus norvegicus
QTL Glom16 Glomerulus QTL 16 Rattus norvegicus
Strain WKY.LEW-(D16Rat88-D16Rat40)/Tja null Rattus norvegicus

Additional Information