Astragalin ameliorates renal injury in diabetic mice by modulating mitochondrial quality control via AMPK-dependent PGC1αpathway  

作　　者：Meng-yao Sun Hui-jing Ye Chen Zheng Zi-jie Jin Yan Yuan Hong-bo Weng 

机构地区：[1]School of Pharmacy,Fudan University,Shanghai,201203,China

出　　处：《Acta Pharmacologica Sinica》2023年第8期1676-1686,共11页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China (grant number 82073859 and 81673658).

摘　　要：Diabetic kidney disease(DKD)is a common microvascular complication of diabetes mellitus,and oxidative stress and mitochondrial dysfunction play an important role in this process.It has been shown that aldose reductase(ALR2)catalyzes NADPH-dependent reduction of glucose to sorbitol,resulting in oxidative stress and mitochondrial dysfunction in diabetic patients.Astragalin(AG),a flavonoid extracted from Thesium chinense Turcz.,shows an inhibitory activity on ALR2.In this study,we investigated the therapeutic effects of AG against renal injury in streptozocin(STZ)-induced diabetic mouse model.Diabetic mice were orally administered AG(5,10 mg·kg^(−1)·d^(−1))for 4 weeks.We showed that AG treatment greatly improved the proteinuria and ameliorated renal pathological damage without affecting the elevated blood glucose in diabetic mice.Furthermore,AG treatment significantly suppressed highly activated ALR2,and reduced oxidative stress in the kidney of diabetic mice and in high glucose and lipids-stimulated HK2 cells in vitro.We demonstrated that AG treatment modulated mitochondrial quality control and ameliorated apoptosis,boosting mitochondrial biogenesis,maintaining mitochondrial dynamic homeostasis,and improving energy metabolism disorder in vivo and in vitro.In high glucose and lipids-stimulated HK2 cells,we found that AG(20μM)restored the phosphorylation level of AMPK,and upregulated the expression and transcriptional activity of PGC1α,whereas treatment with H_(2)O_(2),blockade of AMPK with Compound C or knockdown of AMPKαwith siRNA abolished the protective effect of AG on mitochondrial function,suggesting that antioxidant effects and activation of AMPK-dependent PGC1αpathway might be the molecular mechanisms underlying the protective effects of AG on mitochondrial quality control.We conclude that AG could be a promising drug candidate for the treatment of diabetic renal injury through activating AMPK.

关 键 词：diabetic kidney disease aldose reductase ASTRAGALIN mitochondrial quality control AMPK PGC1α 

分 类 号：R285.5[医药卫生—中药学]