Sphingosine kinase 1 mediates AGEs-induced fibronectin upregulation in diabetic nephropathy

被引：37

作者：

Chen, Cheng ^{[1
,3
]}

Gong, Wenyan ^{[1
]}

Li, Changzheng ^{[2
]}

Xiong, Fengxiao ^{[1
]}

Wang, Shaogui ^{[1
]}

Huang, Junying ^{[1
]}

Wang, Yu ^{[1
]}

Chen, Zhiquan ^{[1
]}

Chen, Qiuhong ^{[1
]}

Liu, Peiqing ^{[1
]}

Lan, Tian ^{[2
]}

Huang, Heqing ^{[1
,3
]}

机构：

[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Lab Pharmacol & Toxicol, Guangzhou 510006, Guangdong, Peoples R China

[2] Guangdong Pharmaceut Univ, Guangzhou 510006, Guangdong, Peoples R China

[3] Natl Local United Engn Lab Drug Screening & Evalu, Guangzhou 510006, Guangdong, Peoples R China

来源：

ONCOTARGET | 2017年 / 8卷 / 45期

基金：

中国国家自然科学基金;

关键词：

AGEs; diabetic nephropathy; sphingosine kinase 1; GMCs; SphK1(-/-) mice; GLYCATION END-PRODUCTS; GLOMERULAR MESANGIAL CELLS; HIGH GLUCOSE; PATHOGENETIC MECHANISMS; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; NRF2/ARE PATHWAY; OXIDATIVE STRESS; EXPRESSION; DISEASE;

D O I：

10.18632/oncotarget.20205

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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.

引用

页码：78660 / 78676

页数：17

共 53 条

[1]

Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720 [J].