A novel compound AB38b attenuates oxidative stress and ECM protein accumulation in kidneys of diabetic mice through modulation of Keap1/Nrf2 signaling  

作　　者：Lei Du Lei Wang Bo Wang Jin Wang Meng Hao Yi-bing Chen Xi-zhi Li Yuan Li Yan-fei Jiang Cheng-cheng Li Hao Yang Xiao-ke Gu Xiao-xing Yin Qian Lu 

机构地区：[1]Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy,Xuzhou Medical University,Xuzhou 221004,China

出　　处：《Acta Pharmacologica Sinica》2020年第3期358-372,共15页中国药理学报（英文版）

基　　金：The work was supported by the National Natural Science Foundation of China(No.81473257);the Qing Lan project,the Natural Science Foundation of Jiangsu Province(No.BK20151155);the“333”Foundation of Jiangsu Province(No.BRA2015329);the Key Natural Science Foundation of Jiangsu Higher Education Institutions of China(No.15KJA310005);the Jiangsu Overseas Research&Training Program for University Young&Middle-aged Teachers and Presidents,the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD);the Science and Technology Project of Xuzhou(No.KC18202).

摘　　要：Extracellular matrix(ECM)deposition following reactive oxygen species(ROS)overproduction has a key role in diabetic nephropathy(DN),thus,antioxidant therapy is considered as a promising strategy for treating DN.Here,we investigated the therapeutic effects of AB38b,a novel syntheticα,β-unsaturated ketone compound,on the oxidative stress(OS)and ECM accumulation in type 2 diabetes mice,and tried to clarify the mechanisms underlying the effects in high glucose(HG,30 mM)-treated mouse glomerular mesangial cells(GMCs).Type 2 diabetes model was established in mice with high-fat diet feeding combined with streptozocin intraperitoneal administration.The diabetic mice were then treated with AB38b(10,20,40 mg·kg^?1·d^?1,ig)or a positive control drug resveratrol(40 mg·kg^?1·d^?1,ig)for 8 weeks.We showed that administration of AB38b or resveratrol prevented the increases in malondialdehyde level,lactate dehydrogenase release,and laminin and type IV collagen deposition in the diabetic kidney.Simultaneously,AB38b or resveratrol markedly lowered the level of Keap1,accompanied by evident activation of Nrf2 signaling in the diabetic kidney.The underlying mechanisms of antioxidant effect of AB38b were explored in HG-treated mouse GMCs.AB38b(2.5?10μM)or resveratrol(10μM)significantly alleviated OS and ECM accumulation in HG-treated GMCs.Furthermore,AB38b or resveratrol treatment effectively activated Nrf2 signaling by inhibiting Keap1 expression without affecting the interaction between Keap1 and Nrf2.Besides,AB38b treatment effectively suppressed the ubiquitination of Nrf2.Taken together,this study demonstrates that AB38b ameliorates experimental DN through antioxidation and modulation of Keap1/Nrf2 signaling pathway.

关 键 词：AB38b RESVERATROL antioxidant diabetic NEPHROPATHY oxidative stress ECM NRF2 Keapl glomerular MESANGIAL cells 

分 类 号：R965[医药卫生—药理学]