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 with control tissues, immunostaining of human DKD biopsies showed an accumulation of SYK⁺ cells and CD68⁺ macrophages with a very similar localization on serial sections. In a model of streptozotocin-induced type 1 diabetes in hypertensive <i>Nos3^-/-</i> 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 wk of diabetes, <i>Nos3^-/-Syk</i>^f/f mice exhibited albuminuria, renal function impairment, glomerulosclerosis, tubular injury, and tubulointerstitial fibrosis. By contrast, diabetic mice with myeloid <i>Syk</i> gene deletion (<i>Nos3^-/-Syk</i>^f/f<i>Csf1r</i>^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 <i>Mmp12</i> and <i>Arg1</i>. 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.<b>NEW & NOTEWORTHY</b> Spleen tyrosine kinase (SYK) was shown to be mainly expressed by infiltrating kidney macrophages in human and experimental diabetic kidney disease (DKD), suggesting a potential role for SYK in the progression of this disease. Furthermore, myeloid <i>Syk</i> deletion suppressed macrophage recruitment, expression of macrophage elastase (<i>Mmp-12</i>), and development of glomerular and interstitial fibrosis in a mouse model of hypertensive DKD.