中国临床医学2025，Vol.32Issue(2)：248-258,11.DOI:10.12025/j.issn.1008-6358.2025.20241329
钠-葡萄糖协同转运蛋白2抑制剂恩格列净改善尿毒症不良心肌重构的效果及机制
Effect of sodium-glucose cotransporter 2 inhibitor empagliflozin in alleviating uremic cardiomyopathy and related mechanism
摘要
Abstract
Objective To investigate the effect of sodium-glucose cotransporter 2 inhibitor(empagliflozin,EMPA)on myocardial remodeling in a mouse uremic cardiomyopathy(UCM)model induced by 5/6 nephrectomy,through the phosphatidylinositol 3 kinase(PI3K)/protein kinase B(PKB/AKT)/p65 signaling pathway.Methods The animals were divided into three groups:Sham group(n=6),UCM group(n=8),and UCM+EMPA group(n=8).A UCM model was established in C57BL/6N mice using the 5/6 nephrectomy.Starting from 5 weeks post-surgery,EMPA or a placebo was administered.After 16 weeks,blood pressure,serum creatinine,blood urea nitrogen,24-hour urine glucose and urine sodium were measured.Cardiac structure and function were assessed by echocardiography.Hematoxylin-eosin(HE)staining and Masson trichrome staining were used to observe pathological changes in the heart and kidneys.Wheat germ agglutinin(WGA)staining was used to evaluate myocardial hypertrophy.The real-time quantitative PCR(RT-qPCR)was used to detect the expression levels of myocardial hypertrophy-and fibrosis-related mRNAs.Western blotting was used to detect the expression levels of PI3K,AKT and p65 in myocardial tissues.Results After 16 weeks,UCM group exhibited significantly higher blood pressure,serum creatinine,blood urea nitrogen than sham group(P＜0.01);UCM+EMPA group exhibited lower blood pressure,serum creatinine,blood urea nitrogen,and higher 24 h urine sodium and glucose than UCM group(P＜0.05).Echocardiographic results showed ventricular remodeling in the UCM group,evidenced by left ventricular wall thickening,left ventricular enlargement,increased left ventricular mass,and decreased systolic function(P＜0.05);ventricular remodeling was alleviated(P＜0.05),though there was no significant improvement in systolic function in UCM+EMPA group.HE and Masson stainings revealed myocardial degeneration,necrosis,and interstitial fibrosis in UCM group(P＜0.01);the myocardial pathology improved with reduced collagen deposition in UCM+EMPA group(P＜0.01).WGA staining confirmed myocardial hypertrophy in UCM group(P＜0.01),while myocardial hypertrophy was alleviated in UCM+EMPA group(P＜0.01).RT-qPCR results showed myocardial hypertrophy-and fibrosis-related genes(NPPA,NPPB,MYH7,COL1A1,COL3A1,TGF-β1)were upregulated in UCM group(P＜0.05),but downregulated in UCM+EMPA group.Western blotting showed PI3K,p-AKT/AKT ratio,and p-p65/p65 ratio were increased in UCM group,but decreased in UCM+EMPA group(P＜0.05).Conclusion EMPA can improve myocardial hypertrophy and fibrosis in the UCM mouse model,and it may play the role through inhibiting the PI3K/AKT/p65 signaling pathway.关键词
尿毒症心肌病/钠-葡萄糖协同转运蛋白2抑制剂/磷脂酰肌醇3激酶/蛋白激酶BKey words
uremic cardiomyopathy/sodium-glucose cotransporter 2 inhibitor/phosphatidylinositol 3 kinase/protein kinase B分类
医药卫生引用本文复制引用
成实,谢烨卿,卢威,许佳瑞,虞勇,陈瑞珍,沈波,丁小强..钠-葡萄糖协同转运蛋白2抑制剂恩格列净改善尿毒症不良心肌重构的效果及机制[J].中国临床医学,2025,32(2):248-258,11.基金项目
上海市科学技术委员会项目(24 DZ2200400,24010701600),上海申康医院发展中心临床科技创新项目(SHDC2202309),复旦大学附属中山医院科研发展基金(2023ZSFZ27).Supported by Shanghai Committee of Science and Technology project(24DZ2200400,24010701600),Shanghai Shenkang Hospital Development Center Clinical Technology Innovation Project(SHDC2202309),and Research and Development Fund of Zhongshan Hospital,Fudan University(2023ZSFZ27). （24 DZ2200400,24010701600）
