RGD Reference Report - A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis. - Rat Genome Database

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A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis.

Authors: Smith, J  McDaid, JP  Bhangal, G  Chawanasuntorapoj, R  Masuda, ES  Cook, HT  Pusey, CD  Tam, FW 
Citation: Smith J, etal., J Am Soc Nephrol. 2010 Feb;21(2):231-6. Epub 2009 Dec 3.
RGD ID: 7175502
Pubmed: PMID:19959716   (View Abstract at PubMed)
PMCID: PMC2834545   (View Article at PubMed Central)
DOI: DOI:10.1681/ASN.2009030263   (Journal Full-text)

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-1beta, 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
crescentic glomerulonephritis  ISOIl1b (Rattus norvegicus)7175502; 7175502 RGD 
crescentic glomerulonephritis  IDA 7175502 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il1b  (interleukin 1 beta)

Genes (Mus musculus)
Il1b  (interleukin 1 beta)

Genes (Homo sapiens)
IL1B  (interleukin 1 beta)


Additional Information