Dr Xiu Xian Chia1, Elyce Ozols1, Dr David Nikolic-Paterson1, Dr Greg Tesch1
1Nephrology Department, Monash Health, Clayton, Australia
Aim: To investigate the role of spleen tyrosine kinase (SYK) in a mouse model of diabetic kidney disease (DKD).
Background: Diabetes is the leading cause of chronic kidney disease in Australia, with limited treatment options. Glomerular macrophage infiltration is an early important process in DKD and correlates with kidney injury. SYK signalling has been shown to play a role in macrophage activation and recruitment, and we hypothesized that its deletion would attenuate DKD.
Methods: Streptozotocin was used to induce diabetes in hypertensive eNos-/-Sykf/f control mice and eNos-/-Sykf/f Csf1rCre mice with selective Syk gene knockout in myeloid cells. Groups of diabetic mice with equivalent levels of blood glucose and glycated haemoglobin (HbA1c) were assessed for renal injury at 15-weeks post streptozotocin.
Results: Compared to non-diabetic mice, the kidneys of diabetic eNos-/-Sykf/f control mice had increased SYK+ mononuclear cells, and increased glomerular macrophages (CD68+ cells 2.2-fold increase, p=0.02). These diabetic mice also had glomerulosclerosis (glomerular collagen IV staining increased 1.6-fold, p<0.01; kidney Collagen I mRNA increased 3.5-fold, p<0.01), and evidence of kidney injury (serum cystatin C increased by 53%, p<0.01; kidney mRNA KIM-1 increased 14.9-fold , p<0.01 and NGAL increased 6.5-fold , p<0.01).
In comparison to diabetic controls, the kidneys of diabetic mice lacking myeloid SYK had reduced SYK+ mononuclear cells, reduced glomerular macrophage infiltration (CD68+ cells decreased 50% , p=0.03) and reduced glomerulosclerosis (glomerular collagen IV staining decreased 24%, p<0.01). However, there was no change in markers of kidney injury, such as serum cystatin C and kidney mRNA levels of KIM-1 and NGAL.
Conclusion: Selective gene deletion of SYK in myeloid cells significantly reduces glomerular macrophage infiltration and glomerulosclerosis in mice with diabetes and hypertension.
Biography:
Bio to come.