Laboratory of Pharmacology & Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Exp Cell Res. 2012 May 1;318(8):936-43. doi: 10.1016/j.yexcr.2012.02.020. Epub 2012 Mar 1.
Accumulation of extracellular matrix including fibronectin in mesangium is one of the major pathologic characteristics in diabetic nephropathy. In the current study, we explored role of sphingosine-1-phosphate (S1P) receptor in fibronectin expression and underlying molecular mechanism. Among five S1P receptors the mRNA level of S1P2 receptor was the most abundant in kidney of diabetic rats and mesangial cells under high glucose condition. S1P augmentation of fibronectin was significantly inhibited by S1P2 receptor antagonist JTE-013 and S1P2-siRNA. S1P-stimulated fibronectin expression was remarkably blocked by ERK1/2 inhibitor PD98059 and p38MAPK inhibitor SB203580. Phospho-ERK1/2 and phospho-p38MAPK level induced by S1P were markedly abrogated by JTE-013 and S1P2-siRNA. In conclusion, S1P2 receptor was significantly up-regulated under diabetic condition. S1P2 receptor mediated fibronectin expression through the activation of S1P-S1P2-MAPK (ERK1/2 and p38MAPK) axis in mesangial cells under high glucose condition, suggesting that it might be a potential therapeutic target for diabetic nephropathy treatment.
细胞外基质的积累，包括纤维连接蛋白在内，是糖尿病肾病的主要病理特征之一。在本研究中，我们探讨了鞘氨醇-1-磷酸（S1P）受体在纤维连接蛋白表达中的作用及其潜在的分子机制。在五种 S1P 受体中，S1P2 受体的 mRNA 水平在糖尿病大鼠肾脏和高糖条件下的系膜细胞中最为丰富。S1P2 受体拮抗剂 JTE-013 和 S1P2-siRNA 显著抑制 S1P 对纤维连接蛋白的增加。ERK1/2 抑制剂 PD98059 和 p38MAPK 抑制剂 SB203580 显著阻断了 S1P 刺激的纤维连接蛋白表达。JTE-013 和 S1P2-siRNA 显著减弱了 S1P 诱导的磷酸化 ERK1/2 和磷酸化 p38MAPK 水平。综上所述，在糖尿病条件下，S1P2 受体显著上调。S1P2 受体通过 S1P-S1P2-MAPK（ERK1/2 和 p38MAPK）轴在高糖条件下介导纤维连接蛋白的表达，表明它可能是治疗糖尿病肾病的潜在治疗靶点。
