An inhibitor of spleen tyrosine kinase suppresses experimental crescentic glomerulonephritis

Abstract

Non-selective inhibitors of spleen tyrosine kinase (SYK) efficiently suppress disease in T cell-dependent models of crescentic glomerulonephritis. However, the therapeutic potential of selective SYK inhibitors in this disease has not been established. In addition, we lack knowledge regarding SYK expression in non-myeloid cells in glomerulonephritis. We addressed these two issues in a rat model of nephrotoxic serum nephritis (NTN) using a SYK inhibitor, GS-492429. Disease was induced in Sprague-Dawley rats (Study 1) or Wistar-Kyoto (WKY) rats (Study 2) by immunization with sheep IgG and administration of sheep anti-rat nephrotoxic serum. Animals were untreated or received GS-492429 (30 mg/kg/bid) or vehicle treatment from 2 h before nephrotoxic serum injection until being killed 3 or 24 h later (Study 1) or 14 days later (Study 2). Two-colour confocal microscopy found that SYK expression in NTN kidney was restricted to myeloid cells and platelets, with no evidence of SYK expression by T cells, mesangial cells, podocytes or tubular epithelial cells. In Study 1, GS-492429 treatment significantly reduced glomerular neutrophil and macrophage infiltration, with protection from glomerular thrombosis and proteinuria. In Study 2, GS-492429 treatment reduced glomerular crescent formation by 70% on day 14 NTN in conjunction with reduced glomerular thrombosis, glomerulosclerosis and tubular damage. This was accompanied by a marked reduction in markers of inflammation (CCL2, TNF-α, NOS2, MMP-12). Importantly, the protective effects of GS-492429 were independent of T cell infiltration and activation and independent of JAK/STAT3 signalling. In conclusion, this study demonstrates that a SYK inhibitor can suppress the development of crescentic glomerulonephritis through effects upon myeloid cells and platelets.

Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model

“…A specific contribution of SYK to neutrophil-and monocyte-mediated glomerular inflammation, however, is suggested by studies in SYKdeficient mice and with alternative pharmacologic inhibitors. 16,34,35 In this study, we have confirmed our previous findings, and those of other groups, that SYK expression is upregulated, and that SYK is activated, at sites of glomerular inflammation in renal AAV. 13,16 Our additional in vivo data provide further evidence that SYK contributes to disease pathogenesis, and that clinical studies of SYK inhibition should be considered.…”

Add-On Cyclic Angiotensin-(1-7) with Cyclophosphamide Arrests Progressive Kidney Disease in Rats with ANCA Associated Glomerulonephritis

“…HIS48-positive neutrophils in the glomeruli, and CD4+ cells within glomeruli, were counted in an average of 25 glomeruli in each kidney sample and expressed as the average number of cells per glomerulus. RECA-1 staining of capillaries in the glomerular tuft was scored as previously described [ 22 ] as follows: 0, normal density of capillaries; 1+, reduced capillary density in <25% of tuft; 2+, reduced capillary density in 25–50% of the tuft; and 3+, reduced capillary density in >50% of the tuft.…”