Research Papers:

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

Cheng Chen, Wenyan Gong, Changzheng Li, Fengxiao Xiong, Shaogui Wang, Junying Huang, Yu Wang, Zhiquan Chen, Qiuhong Chen, Peiqing Liu, Tian Lan and Heqing Huang _

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Oncotarget. 2017; 8:78660-78676. https://doi.org/10.18632/oncotarget.20205

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Cheng Chen1,3,*, Wenyan Gong1,*, Changzheng Li2, Fengxiao Xiong1, Shaogui Wang1, Junying Huang1, Yu Wang1, Zhiquan Chen1, Qiuhong Chen1, Peiqing Liu1, Tian Lan2 and Heqing Huang1,3

1Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China

2Guangdong Pharmaceutical University, Guangzhou 510006, China

3National & Local United Engineering Lab of Drug Screening and Evaluation, Guangzhou 510006, China

*These authors have contributed equally to this study

Correspondence to:

Heqing Huang, email: huangheq@mail.sysu.edu.cn

Tian Lan, email: lantian012345@163.com

Keywords: AGEs, diabetic nephropathy, sphingosine kinase 1, GMCs, SphK1-/- mice

Received: April 16, 2017    Accepted: July 12, 2017    Published: August 10, 2017


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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