| Genetic loci modulate macrophage activity and glomerular damage in experimental glomerulonephritis. | |
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MedLine Citation:
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PMID: 20488952 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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Jacques Behmoaras; Jennifer Smith; Zelpha D'Souza; Gurjeet Bhangal; Ratana Chawanasuntoropoj; Frederick W K Tam; Charles D Pusey; Timothy J Aitman; H Terence Cook |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-20 |
Journal Detail:
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Title: Journal of the American Society of Nephrology : JASN Volume: 21 ISSN: 1533-3450 ISO Abbreviation: J. Am. Soc. Nephrol. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-01 Completed Date: 2010-07-21 Revised Date: 2011-08-25 |
Medline Journal Info:
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Nlm Unique ID: 9013836 Medline TA: J Am Soc Nephrol Country: United States |
Other Details:
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Languages: eng Pagination: 1136-44 Citation Subset: IM |
Affiliation:
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Department of Renal Medicine, Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London, United Kingdom. jacquesb@imperial.ac.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bone Marrow Transplantation Cells, Cultured Disease Models, Animal Genetic Loci / genetics*, physiology* Genetic Predisposition to Disease / genetics Glomerular Mesangium / metabolism, pathology, physiopathology* Glomerulonephritis / genetics*, pathology, physiopathology* Kidney Transplantation Macrophages / pathology, physiology* Male Matrix Metalloproteinase 12 / metabolism Nitric Oxide Synthase Type II / metabolism Rats Rats, Inbred Lew Rats, Inbred WKY Tumor Necrosis Factor-alpha / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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//Medical Research Council; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Tumor Necrosis Factor-alpha; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 3.4.24.65/Matrix Metalloproteinase 12 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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