Publication: Genetic loci modulate macrophage activity and glomerular damage in experimental glomerulonephritis
Issued Date
2010-07-01
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ISSN
15333450
10466673
10466673
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2-s2.0-77954579782
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of the American Society of Nephrology. Vol.21, No.7 (2010), 1136-1144
Suggested Citation
Jacques Behmoaras, Jennifer Smith, Zelpha D'Souza, Gurjeet Bhangal, Ratana Chawanasuntoropoj, Frederick W.K. Tam, Charles D. Pusey, Timothy J. Aitman, H. Terence Cook Genetic loci modulate macrophage activity and glomerular damage in experimental glomerulonephritis. Journal of the American Society of Nephrology. Vol.21, No.7 (2010), 1136-1144. doi:10.1681/ASN.2009090968 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/29613
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Title
Genetic loci modulate macrophage activity and glomerular damage in experimental glomerulonephritis
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Abstract
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-α 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. Copyright © 2010 by the American Society of Nephrology.