Polydatin attenuates AGEs-induced upregulation of fibronectin and ICAM-1 in rat glomerular mesangial cells and db/db diabetic mice kidneys by inhibiting the activation of the SphK1-S1P signaling pathway

Mol Cell Endocrinol. 2016 May 15:427:45-56. doi: 10.1016/j.mce.2016.03.003. Epub 2016 Mar 4.


We previously demonstrated that activation of sphingosine kinase 1 (SphK1)- sphingosine 1- phosphate (S1P) signaling pathway by high glucose (HG) plays a pivotal role in increasing the expression of fibronectin (FN), an important fibrotic component, by promoting the DNA-binding activity of transcription factor activator protein 1 (AP-1) in glomerular mesangial cells (GMCs) under diabetic conditions. As a multi-target anti-oxidative drug, polydatin (PD) has been shown to have renoprotective effects on experimental diabetes. However, whether PD could resist diabetic nephropathy (DN) by regulating SphK1-S1P signaling pathway needs further investigation. Here, we found that PD significantly reversed the upregulated FN and ICAM-1 expression in GMCs exposed to AGEs. Simultaneously, PD dose-dependently inhibited SphK1 levels at the protein expression and kinase activity and attenuated S1P production under AGEs treatment conditions. In addition, PD reduced SphK activity in GMCs transfected with wild-type SphK(WT) plasmid and significantly suppressed SphK1-mediated increase of FN and ICAM-1 levels under normal conditions. Furthermore, we found that the AGEs-induced upregulation of phosphorylation of c-Jun at Ser63 and Ser73 and c-Fos at Ser32, DNA-binding activity and transcriptional activity of AP-1 were blocked by PD. In comparison with db/db model group, PD treatment suppressed SphK1 levels (mRNA, protein expression, and activity) and S1P production, reversed the upregulation of FN, ICAM-1, c-Jun, and c-Fos in the kidney tissues of diabetic mice, and finally ameliorated renal injury in db/db mice. These findings suggested that the downregulation of SphK1-S1P signaling pathway is probably a novel mechanism by which PD suppressed AGEs-induced FN and ICAM-1 expression and improved renal dysfunction of diabetic models.

Keywords: Advanced glycation-end products; Diabetic nephropathy; Fibronectin; Intercellular adhesion molecule-1; Polydatin; Sphingosine kinase 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism*
  • Drugs, Chinese Herbal / pharmacology
  • Female
  • Fibronectins / metabolism*
  • Glomerular Mesangium / drug effects*
  • Glomerular Mesangium / metabolism
  • Glucosides / pharmacology*
  • Glycation End Products, Advanced / antagonists & inhibitors
  • Glycation End Products, Advanced / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Lysophospholipids / antagonists & inhibitors
  • Lysophospholipids / metabolism
  • Male
  • Mice
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects*
  • Sphingosine / analogs & derivatives
  • Sphingosine / antagonists & inhibitors
  • Sphingosine / metabolism
  • Stilbenes / pharmacology*
  • Up-Regulation / drug effects


  • Drugs, Chinese Herbal
  • Fibronectins
  • Glucosides
  • Glycation End Products, Advanced
  • Hypoglycemic Agents
  • Lysophospholipids
  • Stilbenes
  • Intercellular Adhesion Molecule-1
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine
  • polydatin