A role for spleen tyrosine kinase in renal fibrosis in the mouse obstructed kidney.

Abstract Aims Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in the signalling pathways of the B cell receptor, Fcγ-receptor and some leukocyte integrins. However, Syk can also be expressed by some non-haematopoietic cell types, although whether Syk signalling in these cells contributes to the pathogenesis of kidney disease is unknown. To address this question, we examined the function of Syk in antibody-independent renal interstitial fibrosis in the unilateral ureteric obstruction (UUO) model. Main methods Groups of C57BL/6J mice were treated with a selective Syk inhibitor (CC0417, 30 mg/kg/bid), vehicle, or no treatment, from the time of surgery until being killed 7 days later. Key findings A substantial accumulation of interstitial Syk + cells was seen in the UUO kidney. Double staining identified Syk expression by infiltrating macrophages and by a subset of α-SMA + myofibroblasts. CC0417 treatment substantially reduced the Syk + cell population in conjunction with a reduction in both myofibroblast and macrophage accumulation. This was associated with a substantial reduction in collagen IV deposition and mRNA levels of pro-fibrotic (collagen I, collagen IV, fibronectin, α-SMA, TGF-β1 and PAI-1) and pro-inflammatory molecules (MCP-1, TNF-α and NOS2). CC0417 treatment reduced both PDGF-B mRNA levels and Ki67 + proliferating interstitial cells in the UUO kidney. Furthermore, CC0417 inhibited PDGF-AB induced ERK activation and cell proliferation of cultured primary kidney fibroblasts. Significance This study has identified a pathologic role for Syk in renal interstitial fibrosis. Syk inhibitors may have therapeutic potential in chronic fibrotic kidney disease.