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
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
复制标题
虎杖甙通过抑制 SphK1-S1P 信号通路的激活，减弱 AGEs 诱导的大鼠肾小球系膜细胞和 db/db 糖尿病小鼠肾脏中纤连蛋白和 ICAM-1 的上调
DOI：
10.1016/j.mce.2016.03.003
复制
发表时间：
2016-05-15
影响因子：
4.1
通讯作者：
Huang, Heqing
中科院分区：
文献类型：
--
作者：
Chen, Cheng;Huang, Kaipeng;Huang, Heqing
我们之前已经证明，高糖（HG）激活鞘氨醇激酶1 (SphK1)-鞘氨醇1-磷酸（S1P）信号通路在糖尿病患者肾小球系膜细胞（GMCs）中通过促进转录因子激活蛋白1 （AP-1）的dna结合活性，在增加纤维连接蛋白（FN）的表达中起关键作用，FN是重要的纤维化成分。作为一种多靶点的抗氧化药物，聚丹苷（PD）对实验性糖尿病具有保护肾的作用。然而，PD是否通过调节SphK1-S1P信号通路来抵抗糖尿病肾病（DN）还有待进一步研究。在这里，我们发现PD显著逆转了暴露于AGEs的GMCs中FN和ICAM-1的上调表达。同时，在AGEs处理条件下，PD剂量依赖性地抑制SphK1蛋白表达和激酶活性水平，并减弱SIP的产生。此外，PD降低了野生型SphK（WT）质粒转染的gmc中SphK的活性，并在正常条件下显著抑制了sphk1介导的FN和ICAM-1水平的升高。此外，我们发现ages诱导的c-Jun Ser63、Ser73和c-Fos Ser32磷酸化上调、AP-1的dna结合活性和转录活性被PD阻断。与db/db模型组比较，PD治疗可抑制SphK1 mRNA、蛋白表达和活性以及SIP的产生，逆转糖尿病小鼠肾组织中FN、ICAM-1、c-Jun和c-Fos的上调，最终改善db/db小鼠的肾损伤。这些发现提示，下调SphK1-S1P信号通路可能是PD抑制ages诱导的糖尿病模型FN和ICAM-1表达，改善肾功能的新机制。2016爱思唯尔爱尔兰有限公司版权所有。
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 SIP 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 SIP 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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.