Journal
ONCOTARGET
Volume 8, Issue 45, Pages 78660-78676Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20205
Keywords
AGEs; diabetic nephropathy; sphingosine kinase 1; GMCs; SphK1(-/-) mice
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Funding
- Major Science and Technology Project of China [2014ZX09301307-008]
- National Natural Science Foundation of China [81373457, 81573477, 81170676]
- Doctoral Fund Project of the Ministry of Education of China [20130171110097]
- Key Projects of Natural Science Foundation of Guangdong Province [1714050000347, 2016A030311014]
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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.
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