基于Nrf2/HO-1通路研究肾素抑制剂SPH3127对两肾一夹高血压大鼠血压的影响及可能的机制  

Effects of Renin Inhibitor SPH3127 on Blood Pressure in Rats With Experimental Hypertension:Impact on Nrf2/HO-1 Pathway

作　　者：李圆 张昕[1] 马雯 秦春迪 邹琳 李瑜[1] 朱雅泉 LI Yuan;ZHANG Xin;MA Wen;QIN Chundi;ZOU Lin;LI Yu;ZHU Yaquan(Department of Cardiology,The First Affiliated Hospital of Baotou Medical College,Inner Mongolia University of Science and Technology,Baotou 014000,China)

机构地区：[1]内蒙古科技大学包头医学院第一附属医院心功能科,包头014000

出　　处：《中国循环杂志》2023年第8期867-872,共6页Chinese Circulation Journal

基　　金：内蒙古自治区高等学校青年科技英才支持计划(NJYT23075)。

摘　　要：目的:探讨新型肾素抑制剂SPH3127对两肾一夹(2K1C)高血压大鼠血压的影响及可能的机制。方法:将80只雄性SD大鼠随机分为四组:假手术组、高血压模型组、SPH3127组(SPH312710 mg/kg干预的高血压模型)、SPH3127+全反式维甲酸(ATRA)组(SPH312710 mg/kg+ATRA 10 mg/kg干预的高血压模型),每组20只。采用2K1C法建立大鼠高血压模型,按上述分组灌胃及腹腔注射给药,每日1次,连续4周。每次药物干预后2 h测量大鼠的尾动脉收缩压和舒张压,干预4周后检测血清血管紧张素Ⅱ(AngⅡ)水平,并测量胸主动脉活性氧(ROS)含量以及核因子E2相关因子2(Nrf2)、血红素加氧酶-1(HO-1)信使RNA(mRNA)和蛋白相对表达水平。结果:经干预后,SPH3127组大鼠收缩压和舒张压较高血压模型组均显著降低(P均<0.05)。高血压模型组大鼠Nrf2、HO-1 mRNA及蛋白相对表达水平较假手术组均显著降低,SPH3127组大鼠Nrf2、HO-1 mRNA及蛋白相对表达水平较高血压模型组则显著升高,SPH3127+ATRA组大鼠应用Nrf2抑制剂ATRA后Nrf2和HO-1表达受抑制,此时SPH3127对高血压模型大鼠的保护作用减弱(P均<0.05)。高血压模型组大鼠的血清AngⅡ水平和胸主动脉ROS含量较假手术组均升高,SPH3127组大鼠的血清AngⅡ水平和胸主动脉ROS含量较高血压模型组均显著下降,SPH3127+ATRA组大鼠的胸主动脉ROS含量较SPH3127组有所升高,但仍明显低于高血压模型组(P均<0.05)。结论:SPH3127可通过抑制肾素、减少AngⅡ生成而有效降低血压,可能与其激活Nrf2/HO-1通路、减轻氧化应激有关。Objectives:To investigate the effect and possible mechanism of a novel renin inhibitor SPH3127 on blood pressure in hypertensive rats induced by two kidneys and one clip.Methods:Eighty male SD rats were randomly divided into 4 groups(n=20 each):sham operation group,hypertension model group,SPH3127 group(hypertension model treated with SPH312710 mg/kg per day for 4 weeks),SPH3127+all trans retinoic acid(ATRA)group(hypertension model treated with SPH312710 mg/kg per day and ATRA 10 mg/kg per day for 4 weeks).The rat hypertension model was established by 2-Kidney-1-Clip(2K1C)method.Caudal systolic blood pressure and diastolic blood pressure were measured at 2 h after each drug intervention.After 4 weeks of intervention,serum angiotensinⅡ(AngⅡ)and reactive oxygen species(ROS)levels and the mRNA and protein expression levels of nuclear factor erythroid 2-related factor 2(Nrf2)and heme oxygenase-1(HO-1)in thoracic aorta were measured.Results:After intervention,the systolic and diastolic blood pressures in SPH3127 group were significantly lower than those in the hypertension model group(both P<0.05).The relative expression of Nrf2 and HO-1 mRNA and protein in the hypertension model group were significantly lower than those in the sham operation group.The relative expression of Nrf2 and HO-1 mRNA and protein in SPH3127 group were significantly higher than those in the hypertension model group.The expression of Nrf2 and HO-1 in SPH3127+ATRA group were inhibited after Nrf2 inhibitor ATRA intervention,the protective effect of SPH3127 on hypertensive model rats was weakened(all P<0.05).The serum Ang II level and thoracic aortic ROS content in the hypertension model group were higher than those in the sham operation group,serum Ang II level and ROS content in thoracic aorta of rats in SPH3127 group were significantly lower than those in hypertension model group(all P<0.05).The ROS content of thoracic aorta in SPH3127+ATRA group was higher than that in SPH3127 group,but still significantly lower than that in the hypertensi

关 键 词：肾素 高血压 核因子E2相关因子2 血红素加氧酶-1 氧化应激 

分 类 号：R54[医药卫生—心血管疾病]