A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis.
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.
Smith
Jennifer
J
Imperial College Kidney and Transplant Institute, Division of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
McDaid
John P
JP
Bhangal
Gurjeet
G
Chawanasuntorapoj
Ratana
R
Masuda
Esteban S
ES
Cook
H Terence
HT
Pusey
Charles D
CD
Tam
Frederick W K
FW
D000631:Aminopyridines; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines; D051381:Rats; D011921:Rats, Inbred WKY; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase
D000631:Aminopyridines; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; C510788:N4-(2,2-dimethyl-3-oxo-4H-pyrid(1,4)oxazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; C523665:fostamatinib