姜黄素通过鞘氨醇激酶-1-一磷酸鞘氨醇信号通路抗糖尿病大鼠肾脏纤维化的研究

Curcumin ameliorated diabetic rat renal fibrosis through inhibition of SphK1-S1P signaling pathway

目的:研究姜黄素对链脲霉素(STZ)诱导的糖尿病大鼠肾脏损伤的改善作用,及其对糖尿病大鼠肾脏鞘氨醇激酶-1-一磷酸鞘氨醇(SphK1-S1P)信号通路和肾脏纤维化的抑制作用。方法:本研究采用STZ诱导的糖尿病大鼠,观察灌胃给药0.15g/kg的姜黄素对糖尿病大鼠肾脏功能和病理形态的影响,对大鼠肾组织的SphK1、S1P、纤维连接蛋白(FN)及转化生长因子(TGF)-β1等指标的影响。用Real-time PCR和Western blotting方法检测SphK1,FN和TGF-β1的表达;用LC-MS/MS方法检测SphK1活性和S1P含量。结果:0.15g/kg的姜黄素能够明显改善糖尿病大鼠的肾功能与肾脏病理变化,明显降低糖尿病大鼠肾脏SphK1的表达和活性以及S1P的含量,进而抑制SphK1-S1P诱导的FN和TGF-β1的表达。结论:姜黄素对于糖尿病肾脏纤维化的改善作用机制可能与其抑制肾脏SphK1-S1P信号通路密切相关。

Objective： To evaluate the inhibitory effect of curcumin on the sphingosine kinase 1 （SphK1）-sphingosine 1-phosphate （SIP） signaling pathway and the protective effect of curcumin on streptozocin （STZ）-induced diabetic renal fibrosis in SD rats. Methods： STZ-induced diabetic rats were treated orally with cureumin （0.15g/kg·day） to explore the changes of renal function and pathomorphism, and measure the expression of SphK1, S1 P, FN, and TGF-β1 in renal tissue. Western blot assay and real-time PCR assay were applied to detect the protein and mRNA expression levels of SphK1, FN, and TGF-β1. LC-MS/MS method was used to detect the SphK1 activity and S1P production. Results： Cureumin（0.15g/kg·day） significantly attenuated the renal dysfunction and pathological changes in diabetic rats. In addition, cureumin markedly down-regulated the expression and activity of SphKl, as well as SIP production, and therefore, decreased SphKI-SIP pathway-mediated upregulation of FN and TGF-β1 levels. Conclusion： The protective effects of cumumin on diabetic renal injury are closely associated with the inhibited activation of SphK1-S1P pathway.