title: 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.
abstract: 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.
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Kaipeng
authors.initials: K
authors.lastname: Huang
authors.affiliation: Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Hao
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Junying
authors.initials: J
authors.lastname: Huang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Fengxiao
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.affiliation: Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: huangheq@mail.sysu.edu.cn.
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D004365:Drugs, Chinese Herbal; D005353:Fibronectins; D005960:Glucosides; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D018799:Intercellular Adhesion Molecule-1; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D013267:Stilbenes; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C058229:polydatin
keywords: Advanced glycation-end products; Diabetic nephropathy; Fibronectin; Intercellular adhesion molecule-1; Polydatin; Sphingosine kinase 1