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

作　　者：成实 谢烨卿 卢威 许佳瑞 虞勇 陈瑞珍 沈波 丁小强 CHENG Shi;XIE Yeqing;LU Wei;XU Jiarui;YU Yong;CHEN Ruizhen;SHEN Bo;DING Xiaoqiang(Department of Nephrology,Zhongshan Hospital,Fudan University,Shanghai Medical Center of Kidney Disease,Hemodialysis Quality Control Center of Shanghai,Shanghai 200032,China;Department of Cardiology,Zhongshan Hospital,Fudan University,Shanghai 200032,China;Shanghai Institute of Kidney Disease and Dialysis,Shanghai Key Laboratory of Kidney Disease and Dialysis,Shanghai 200032,China)

机构地区：[1]复旦大学附属中山医院肾内科,上海市肾脏疾病临床医学中心,上海市血液透析质量控制中心,上海200032 [2]复旦大学附属中山医院心血管病研究所,上海200032 [3]上海市肾病与透析研究所,上海市肾脏疾病与血液净化重点实验室,上海200032

出　　处：《中国临床医学》2025年第2期248-258,共11页Chinese Journal of Clinical Medicine

基　　金：上海市科学技术委员会项目(24DZ2200400,24010701600);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)。

摘　　要：目的探讨钠-葡萄糖协同转运蛋白2抑制剂(恩格列净;empagliflozin,EMPA)通过磷脂酰肌醇3激酶(phosphatidylinositol 3 kinase,PI3K)/蛋白激酶B(protein kinase B,PKB/AKT)/p65信号通路对5/6肾切除术诱导的小鼠尿毒症心肌病(uremic cardiomyopathy,UCM)模型心肌重构的影响。方法将动物分为假手术组(Sham组,n=6)、模型组(UCM组,n=8)和治疗组(UCM+EMPA组,n=8)。采用5/6肾切除术构建C57BL/6N小鼠UCM模型。术后5周起给予EMPA或安慰剂干预。术后16周,测定血压、血清肌酐、血尿素氮、24 h尿葡萄糖及尿钠,利用心脏超声评估心脏结构及功能。采用苏木精-伊红(hematoxylin-eosin,HE)染色和Masson染色观察心脏及肾脏病理改变。采用麦胚芽凝集素(wheat germ agglutinin,WGA)染色检测心肌肥厚。采用实时荧光定量PCR(real-time quantitative PCR,RTqPCR)检测心肌肥厚及纤维化相关mRNA表达水平。采用Western印迹检测心肌组织PI3K、AKT、p65蛋白表达。结果术后16周,UCM组小鼠血压、血清肌酐、血尿素氮较Sham组升高(P<0.01);UCM+EMPA组血压、血清肌酐、血尿素氮较UCM组下降,24 h尿葡萄糖及尿钠较UCM组增加(P<0.05)。心脏超声结果显示UCM组心室重构,表现为左心室壁增厚、左心室扩大、左心质量增加和收缩功能下降(P<0.05);UCM+EMPA组心室重构缓解(P<0.05),收缩功能无明显改善。HE和Masson染色显示,UCM组发生心肌细胞变性坏死及间质纤维化(P<0.01);UCM+EMPA组心肌病理表现减轻,胶原沉积减少(P<0.01)。WGA染色结果证实UCM组心肌肥大(P<0.01),UCM+EMPA组心肌肥大减轻(P<0.01)。RT-qPCR显示,UCM组心肌肥厚(NPPA、NPPB、MYH7)和纤维化(COL1A1、COL3A1、TGF-β1)相关mRNA表达上调(P<0.05),UCM+EMPA组均降低(P<0.05)。Western印迹显示,UCM组心肌组织PI3K水平、p-AKT/AKT比值、p-p65/p65比值升高(P<0.01),UCM+EMPA组均降低(P<0.05)。结论EMPA干预可改善UCM小鼠心肌肥厚及纤维化,可能与其抑制PI3K/AKT/p65信号通路相�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

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B 

分 类 号：R692[医药卫生—泌尿科学] R541.9[医药卫生—外科学]