Spleen tyrosine kinase signaling in myeloid cells promotes macrophage infiltration, glomerulosclerosis and interstitial fibrosis in diabetic kidney disease.

Macrophages have been implicated in causing renal injury in diabetic kidney disease (DKD). Spleen tyrosine kinase (Syk) plays an important role in signaling via a number of cell surface receptors that promote recruitment and activation of myeloid cells, but whether SYK signaling is involved in DKD is unknown. Therefore, we examined the role of SYK in human and experimental DKD. Compared to control tissues, immunostaining of human DKD biopsies showed an accumulation of Syk+ cells and CD68+ macrophages with a very similar localisation on serial sections. In a model of streptozotocin-induced type 1 diabetes in hypertensive Nos3 -/- mice, there was a significant increase in the number of glomerular Syk+ cells and Cd68+ cells, with double staining showing that most Syk+ cells were Cd68+ macrophages. After 15 weeks of diabetes, Nos3 -/- Syk f/f mice exhibited albuminuria, renal function impairment, glomerulosclerosis, tubular injury, and tubulointerstitial fibrosis. By contrast, diabetic mice with myeloid Syk gene deletion ( Nos3 -/- Syk f/f Csf1r Cre ) exhibited a significant reduction in glomerular Syk+ cell and Cd68+ macrophage accumulation, glomerulosclerosis and tubulointerstitial fibrosis - which were associated with reduced mRNA levels of Mmp12 and Arg1. However, albuminuria, renal function impairment and tubular injury were unaffected. In conclusion, we have shown that SYK is predominantly expressed by macrophages in DKD and that Syk facilitates macrophage accumulation and activation in DKD resulting in glomerulosclerosis and tubulointerstitial fibrosis.