Fisetin treatment alleviates kidney injury in mice with diabetes-exacerbated atherosclerosis through inhibiting CD36/fibrosis pathway  

作　　者：Ting-feng Zou Zhi-gang Liu Pei-chang Cao Shi-hong Zheng Wen-tong Guo Tian-xiang Wang Yuan-li Chen Ya-jun Duan Qing-shan Li Chen-zhong Liao Zhou-ling Xie Ji-hong Han Xiao-xiao Yang 

机构地区：[1]Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes,School of Food and Biological Engineering,Hefei University of Technology,Hefei,230601,China [2]College of Life Sciences,Key Laboratory of Medicinal Chemical Biology,Key Laboratory of Bioactive Materials of Ministry of Education,Nankai University,Tianjin,300071,China

出　　处：《Acta Pharmacologica Sinica》2023年第10期2065-2074,共10页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(NSFC)Grants 81973316 to JHH;the Major Special Science and Technology Project of Anhui Province(202003a07020015)to QSL;the Open Fund of Tianjin Central Hospital of Gynecology Obstetrics/Tianjin Key Laboratory of Human Development and Reproductive Regulation(2021XHY01)to XXY.

摘　　要：Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR−/−) mice. Diabetes was induced in LDLR−/− mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor β (TGFβ)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent

关 键 词：diabetic nephropathy fibrosis ATHEROSCLEROSIS TGFβ/(Smad2/3) CD36 FISETIN LDLR−/−mice HK-2 cells 

分 类 号：R285.5[医药卫生—中药学]