FXR激动剂GW4064改善他克莫司诱导的移植术后糖尿病

FXR agonist GW4064 ameliorates tacrolimus-induced abnormalities in glucose metabolism

目的:研究他克莫司诱导的移植术后糖尿病在小鼠肾脏中相关糖代谢基因的表达及法尼酯X受体(FXR)激活调节葡萄糖代谢的相关机制。方法:用他克莫司和他克莫司+FXR激动剂(GW4064)分别处理HK-2细胞系并设置对照组,72 h以后检测细胞中FXR、小异二聚体伴侣-1(SHP-1)、磷酸烯醇丙酮酸羧激酶(PEPCK)、葡萄糖转运蛋白-2(GLUT2)的基因表达水平。用他克莫司和他克莫司+FXR激动剂分别将C57BL/6J雄性小鼠灌胃12周,对照组给予生理盐水,观察小鼠体重和血糖变化;动物处理后,分别检测FXR、SHP-1、PEPCK、GLUT2等基因的表达。结果:在细胞实验中,与对照组相比,他克莫司治疗组的FXR、SHP-1、GLUT2基因表达下降(P<0.05),PEPCK基因的表达明显上调(P<0.05)。在动物实验中,与对照组相比,他克莫司治疗组的血糖值明显增高(P<0.05),他克莫司+FXR激动剂联合干预组的血糖值显著下降(P<0.05),小鼠肾脏的FXR、SHP-1、GLUT2基因表达上调(P<0.05),PEPCK基因的表达显著下降(P<0.05)。结论:FXR激动剂能够改善他克莫司诱导移植术后糖代谢异常。因此,FXR可能是防治移植术后糖尿病的潜在新靶点。

AIM:To investigate the expression of glucose metabolism genes associated with tacrolimus-induced post-transplant diabetes in the mouse kidney and the mechanisms involved in the regulation of glucose metabolism by farnesylate X(FXR)receptor activator.METHODS:The gene expression levels of FXR,small heterodimeric partner-1(SHP-1),phosphoenolpyruvate carboxykinase(PEPCK),and glucose transporter protein-2(GLUT2)were measured after 72 h in HK-2 cell lines treated with tacrolimus and tacrolimus+FXR agonist(GW4064)and control groups,respectively.C57BL/6J male mice were gavaged with tacrolimus and tacrolimus+FXR agonist for 12 weeks,respectively,and the control group was given saline to observe the changes in body weight and blood glucose;after the animals were treated,the gene expression levels of FXR,SHP-1,PEPCK,and GLUT2 were detected,respectively.RESULTS:In cellular experiments,the expression of FXR,SHP-1 and GLUT2 genes was decreased in the tacrolimus-treated group(P<0.05)and the expression of the PEPCK gene was significantly upregulated compared with the control group(P<0.05).In animal experiments,compared with the control group,the blood glucose values were significantly increased in the tacrolimus-treated group and significantly decreased in the tacrolimus+FXR agonist combination intervention group(P<0.05),and the expression of FXR,SHP-1 and GLUT2 genes were upregulated(P<0.05)and the expression of PEPCK genes was significantly decreased in the mice kidney(P<0.05).CONCLUSION:FXR agonists can improve tacrolimus-induced abnormal glucose metabolism after transplantation.Therefore,FXR may be a potential new target for the prevention and treatment of post-transplant diabetes.