黄芪甲苷对阿德福韦酯致肾损伤的保护作用和机制研究

Protective effect and mechanism of astragaloside IV on kidney injury induced by adefovir dipivoxil

目的:本实验旨在研究黄芪甲苷(astragaloside IV,As)对阿德福韦酯(adefovir dipivoxil,Adv)致肾损伤的保护作用,探究其可能的作用机制。方法:将50只SD雄性大鼠按数字表法随机分为正常组(normal),Adv肾损伤组(30 mg·kg^(-1)·d^(-1)),As低、中、高剂量干预组(10,20,30 mg·kg^(-1)·d^(-1))。通过测定血浆生化指标比较各组肾功能差异;Masson染色评价各组肾小管上皮细胞病理学改变;利用UHPLC-MS代谢组学方法检测各组大鼠血浆内源性代谢物的变化,筛选出差异代谢物。结果:与正常组相比,Adv组肌酐值显著升高,肾损伤严重。而As可显著降低肌酐值和改善肾小管上皮细胞病理学形态,有效干预Adv致肾损伤。Adv组大鼠血浆共发现28个差异代谢物,As可显著逆转16个代谢物的变化。主要涉及与能量代谢相关的苯丙氨酸、酪氨酸和色氨酸代谢通路、泛醌和其他萜烯-醌代谢通路,与氧化应激相关的谷胱甘肽代谢通路。结论:本研究提示As保护Adv致肾损伤的机制与改善细胞供能,减少氧化应激对细胞的损害密切相关。本研究为阿德福韦酯治疗慢性乙型肝炎(CHB)时利用黄芪作为减毒增效的治疗策略提供了基础依据。

OBJECTIVE To explore the protective effect of astragaloside(astragaloside IV,As)on kidney injury induced by adefovir dipivoxil(adefovir dipivoxil,Adv)and elucidate its possible mechanism.METHODS A total of 50 Sprague-Dawley male rats were randomly divided into the groups of normal,adefovir dipivoxil nephropathy(Adv 30 mg·kg^(-1)·d^(-1))and astragaloside IV low/middle/high dose intervention(As10/As20/As30 mg·kg^(-1)·d^(-1)).The differential renal functions were compared by measuring plasma biochemical parameters;the pathological changes of renal tubular epithelial cells evaluated by Masson staining;the changes of plasma endogenous metabolites detected by UHPLC-MS metabonomics and differential metabolites screened.RESULTS The creatinine level of Adv group was significantly higher than that of normal group and kidney injury was more severe.As could significantly decrease creatinine level,improve the pathological morphology of renal tubular epithelial cells and effectively interfere with kidney injury induced by adefovir dipivoxil.A total of 28 differential plasma metabolites were detected in Adv group and astragaloside IV could significantly reverse the changes of 16 metabolites.It mainly involved the phenylalanine,tyrosine and tryptophan metabolic pathways related to energy metabolism,ubiquione and other terpene-quinone metabolic pathways and glutathione metabolic pathways related to oxidative stress.CONCLUSION The mechanism of astragaloside on kidney injury induced by adefovir dipivoxil is closely correlated with improving cell energy supply and reducing cell damage caused by oxidative stress.This study provides rationales for using astragalus as an attenuated and synergistic therapeutic strategy in the treatment of chronic hepatitis B(CHB)with adefovir dipivoxil.