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Title: A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis
Authors: Jennifer Smith
John P. McDaid
Gurjeet Bhangal
Ratana Chawanasuntorapoj
Esteban S. Masuda
H. Terence Cook
Charles D. Pusey
Frederick W.K. Tam
Hammersmith Hospital
Mahidol University
Rigel Pharmaceuticals Inc.
Keywords: Medicine
Issue Date: 1-Feb-2010
Citation: Journal of the American Society of Nephrology. Vol.21, No.2 (2010), 231-236
Abstract: Antibody-mediated glomerulonephritis, including that resulting from immune complexes, is an important cause of renal failure and is in need of more specific and effective treatment. Binding of antibody or immune complexes to Fc receptors activates intracellular signal transduction pathways, including spleen tyrosine kinase (Syk), leading to the production of inflammatory cytokines. We examined the effect of R788 (fostamatinib disodium), an oral prodrug of the selective Syk inhibitor R406, in nephrotoxic nephritis in Wistar-Kyoto rats. Treatment with R788 reduced proteinuria, tissue injury, glomerular macrophage and CD8+cell numbers, and renal monocyte chemoattractant protein-1 (MCP-1) and IL-1β, even when we started treatment after the onset of glomerulonephritis. When we administered R788 from days 4 to 10, glomerular crescents reduced by 100% (P < 0.01) compared with the vehicle group. When we administered R788 treatment from days 7 to 14, established glomerular crescents reversed (reduced by 21%, P < 0.001), and renal function was better than the vehicle group (P < 0.001). In vitro, R406 downregulated MCP-1 production from mesangial cells and macrophages stimulated with aggregated IgG. These results suggest that Syk is an important therapeutic target for the treatment of glomerulonephritis. Copyright © 2010 by the American Society of Nephrology.
ISSN: 15333450
Appears in Collections:Scopus 2006-2010

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