Trimetazidine (TMZ), as a metabolic regulator, is effective in treatment of coronary atherosclerotic heart disease with rare side effects in the clinic for long years. Interestingly, studies have shown that TMZ protects against several acute kidney injuries (AKI). However, the effect of TMZ on chronic kidney diseases (CKD) remains unknown. This study aimed to investigate the role of TMZ in diabetic nephropathy (DN) and its potential mechanisms. A rat model of DN was established in male Sprague-Dawley rats by streptozotocin (STZ) intraperitoneal injection. Experimental rats were separated into three groups: control, DN and DN + TMZ treatment. Metabolic parameters, pathological features and renal function markers were evaluated after 20 weeks of diabetes induction.In vitroexperiments, the effect of TMZ on high fat and high glucose (HFG) induced or TGF beta 1-induced epithelial-to-mesenchymal transition (EMT) was examined in HK-2 cells. Our results showed that TMZ could maintain renal function without affecting hemodynamic and plasma metabolic levels in diabetic rats. The effect was associated with a reversion of pathological progression of DN, especially for tubulointerstitial fibrosis. EMT is an important contributor to renal fibrosis. In this study, we investigated the role of TMZ in the process of EMT in DN. Mechanistically; TMZ attenuated HFG-induced EMT by relieving oxidative stressviadeacetylation forkhead box O1 (FoxO1) in a Sirt1-dependent pathway. And it suppressed TGF beta 1-induced EMT by deacetylating Smd4 in a Sirt1-dependent manner. Moreover, our study found that TMZ upregulated Sirt1 expression by increasing the expression of nicotinamide phosphoribosyl transferase (Nampt), which is a rate limiting enzyme for nicotinamide adenine dinucleotide (NAD(+)) generation by salvage pathway. And the increased NAD(+)promoted Sirt1 expression. In conclusion, TMZ can prevent renal dysfunction and pathogenesis of tubulointerstitial fibrosis in DN, partly by inhibition of EMTviaFoxO1/ROS pathway and TGF beta/Smad pathway in a Nampt/NAD(+)/Sirt1 dependent manner.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81570367, 81900341]
第一作者单位：[1]Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Div Cardiol,Dept Internal Med, Wuhan, Peoples R China[2]Huazhong Univ Sci & Technol, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan, Peoples R China
通讯作者：
通讯机构：[1]Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Div Cardiol,Dept Internal Med, Wuhan, Peoples R China[2]Huazhong Univ Sci & Technol, Hubei Key Lab Genet & Mol Mech Cardiol Disorders, Wuhan, Peoples R China
推荐引用方式(GB/T 7714)：
yang yong,wang yong,he zuowen,et al.Trimetazidine Inhibits Renal Tubular Epithelial Cells to Mesenchymal Transition in Diabetic RatsviaUpregulation of Sirt1[J].FRONTIERS IN PHARMACOLOGY.2020,11:doi:10.3389/fphar.2020.01136.
APA：
yang,yong,wang,yong,he,zuowen,liu,yunchang,chen,chen...&wang,hong.(2020).Trimetazidine Inhibits Renal Tubular Epithelial Cells to Mesenchymal Transition in Diabetic RatsviaUpregulation of Sirt1.FRONTIERS IN PHARMACOLOGY,11,
MLA：
yang,yong,et al."Trimetazidine Inhibits Renal Tubular Epithelial Cells to Mesenchymal Transition in Diabetic RatsviaUpregulation of Sirt1".FRONTIERS IN PHARMACOLOGY 11.(2020)
