PMID- 19959716
OWN - NLM
STAT- MEDLINE
DCOM- 20100316
LR  - 20220318
IS  - 1533-3450 (Electronic)
IS  - 1046-6673 (Print)
IS  - 1046-6673 (Linking)
VI  - 21
IP  - 2
DP  - 2010 Feb
TI  - A spleen tyrosine kinase inhibitor reduces the severity of established 
      glomerulonephritis.
PG  - 231-6
LID - 10.1681/ASN.2009030263 [doi]
AB  - 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.
FAU - Smith, Jennifer
AU  - Smith J
AD  - Imperial College Kidney and Transplant Institute, Division of Medicine, 
      Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
FAU - McDaid, John P
AU  - McDaid JP
FAU - Bhangal, Gurjeet
AU  - Bhangal G
FAU - Chawanasuntorapoj, Ratana
AU  - Chawanasuntorapoj R
FAU - Masuda, Esteban S
AU  - Masuda ES
FAU - Cook, H Terence
AU  - Cook HT
FAU - Pusey, Charles D
AU  - Pusey CD
FAU - Tam, Frederick W K
AU  - Tam FW
LA  - eng
GR  - G0400443/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20091203
PL  - United States
TA  - J Am Soc Nephrol
JT  - Journal of the American Society of Nephrology : JASN
JID - 9013836
RN  - 0 (Aminopyridines)
RN  - 0 (Ccl2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Morpholines)
RN  - 0 
      (N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine)
RN  - 0 (Oxazines)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (Syk Kinase)
RN  - EC 2.7.10.2 (Syk protein, rat)
RN  - SQ8A3S5101 (fostamatinib)
SB  - IM
MH  - Aminopyridines
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Disease Models, Animal
MH  - Glomerulonephritis/*metabolism/pathology/*physiopathology
MH  - Interleukin-1beta/metabolism
MH  - Intracellular Signaling Peptides and Proteins/*antagonists & 
      inhibitors/metabolism
MH  - Macrophages/drug effects/metabolism/pathology
MH  - Mesangial Cells/drug effects/metabolism/pathology
MH  - Morpholines
MH  - Oxazines/*pharmacology
MH  - Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism
MH  - Pyridines/*pharmacology
MH  - Pyrimidines
MH  - Rats
MH  - Rats, Inbred WKY
MH  - *Severity of Illness Index
MH  - Signal Transduction/physiology
MH  - Syk Kinase
PMC - PMC2834545
EDAT- 2009/12/05 06:00
MHDA- 2010/03/17 06:00
PMCR- 2011/02/01
CRDT- 2009/12/05 06:00
PHST- 2009/12/05 06:00 [entrez]
PHST- 2009/12/05 06:00 [pubmed]
PHST- 2010/03/17 06:00 [medline]
PHST- 2011/02/01 00:00 [pmc-release]
AID - ASN.2009030263 [pii]
AID - 2009030263 [pii]
AID - 10.1681/ASN.2009030263 [doi]
PST - ppublish
SO  - J Am Soc Nephrol. 2010 Feb;21(2):231-6. doi: 10.1681/ASN.2009030263. Epub 2009 
      Dec 3.