Abstract
Activation of sphingosine kinase 1 (SphK1) signaling pathway mediates fibronectin (FN) upregulation in glomerular mesangial cells (GMCs) under high glucose (HG) condition. However, the roles of SphK1 in advanced glycation end products (AGEs)-induced DN have not been elucidated. Here we show that AGEs upregulated FN and SphK1 and SphK1 activity. Inhibition of SphK1 signaling attenuated AGEs-induced FN synthesis in GMCs. Inhibition of AGE receptor (RAGE) signaling reduced the upregulation of FN and SphK1 and SphK1 activity in GMCs induced by AGEs. Treatment of aminoguanidine ameliorates the renal injury and fibrosis in STZ-induced diabetic mice and attenuated SphK1 expression and activity in diabetic mouse kidneys. The renal injury and fibrosis in diabetic SphK1-/- mice was significantly attenuated than WT mice. Furthermore, AGEs upregulated SphK1 by reducing its degradation and prolonging its half-life. Conclusion: SphK1 mediates AGEs-induced FN synthesis in GMCs and diabetic mice under hyperglycemic condition.
Highlights
Diabetic nephropathy (DN) is a major cause of endstage renal failure, contributing to the overall morbidity and mortality in diabetic patients [1, 2]
We previously demonstrated that activation of the sphingosine kinase 1 (SphK1)-Sphingosine 1-phosphate (S1P) signaling pathway increased the FN upregulation and that the function of the SphK1-S1P signaling pathway is closely correlated with activator protein 1 (AP-1) activation [26, 27]
SphK1 mediated the upregulation of FN in glomerular mesangial cells (GMCs) induced by advanced glycation end products (AGEs)
Summary
Diabetic nephropathy (DN) is a major cause of endstage renal failure, contributing to the overall morbidity and mortality in diabetic patients [1, 2]. Proliferation and hypertrophy of glomerular mesangial cells (GMCs) and accumulation of extracellular matrix components such as fibronectin (FN), contribute to the expansion of mesangial area and the thickening of glomerular basement membrane (GBM), leading to renal dysfunction and fibrosis in diabetic patients with nephropathy [4,5,6]. AGEs break the interaction between matrix and matrix or matrix and cell, as well as intracellular signaling pathways, and disturbs the physiological structure of kidney in diabetes [12, 13]. The molecular mechanisms responsible for the induction of DN by AGEs have not been fully understood
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