标题：福辛普利联合非诺贝特对DM小鼠视网膜Nrf2及HRD1表达的影响

      作者：高亚丰，祁军利，高莉    延安大学附属医院药剂经销科，陕西 延安 716000

      卷次： 2019年30卷13期

      【摘要】 目的 探讨福辛普利联合非诺贝特对糖尿病(DM)小鼠视网膜核因子E2相关因子2 (Nrf2)及甲基戊二酰辅酶A还原酶降解蛋白1 (HRD1)表达的影响。方法 选择150只SD雄性小鼠，采用随机数表法分为空白对照组(假造模)、模型对照组(DM模型)、福辛普利给药组(20 mg·kg-1·d-1福辛普利干预)、非诺贝特给药组(400 mg·kg-1·d-1非诺贝特干预)和联合给药组(20 mg·kg-1·d-1福辛普利与400 mg·kg-1·d-1非诺贝特联合干预)，每组30只。采用裂隙灯检查各组小鼠的晶状体浑浊程度，采用实时荧光定量PCR检测视网膜Nrf2及HRD1 mRNA的表达水平，采用Western blot方法检测视网膜Nrf2及HRD1蛋白表达水平，采用TUNEL染色法检测视网膜组织细胞凋亡TUNEL指数，视网膜丙二醛(MDA)、血管内皮生长因子(VEGF)浓度与谷胱甘肽过氧化物酶(GSH-PX)、超氧化物歧化酶(SOD)、活性氧(ROS)酶活性采用ELISA法检测。对五组小鼠检测的指标进行比较。结果 空白对照组小鼠晶状体无浑浊，其余四组小鼠晶状体均可见不同程度浑浊，五组小鼠晶状体浑浊程度比较差异有统计学意义(P<0.05)；五组小鼠视网膜中Nrf2及HRD1 mRNA表达及其蛋白水平比较差异均有统计学意义(P<0.05)，其中，空白对照组表达最高，联合给药组次之，单药给药组再次，模型对照组表达最低；五组小鼠视网膜组织细胞凋亡TUNEL指数比较差异有统计学意义(P<0.05)，其中模型对照组最高，随后从高至低依次为福辛普利给药组、非诺贝特给药组、联合给药组和空白对照组；五组小鼠视网膜组织中的MDA、VEGF浓度与GSH-PX、SOD、ROS酶活性比较差异均有统计学意义(P<0.05)，GSH-PX、SOD在空白对照组中活性最高，MDA、VEGF浓度、ROS活性最低，联合给药组次之，单药给药组再次，模型对照组最高或最低。结论 福辛普利联合非诺贝特可通过有效增加DM小鼠视网膜Nrf2和HRD1的表达水平来降低氧化应激损伤和内质网应激水平，进而延缓DM进程，改善糖尿病小鼠视网膜功能。
      【关键词】 视网膜；福辛普利；非诺贝特；核因子E2相关因子2；甲基戊二酰辅酶A还原酶降解蛋白1
      【中图分类号】 R-332 【文献标识码】 A 【文章编号】 1003—6350（2019）13—1647—05

Effect of Phu Simpson Leigh combined with fenofibrate on the expression of Nrf2 and HRD1 in the retina of DMmice.
GAO Ya-feng, QI Jun-li, GAO Li. Department of Pharmaceutical Distribution, Yan'an University Affiliated Hospital,Yanan 716000, Shaanxi, CHINA
【Abstract】 Objective To investigate the effect of fosinopril combined with fenofibrate on the expression of nu-clear factor-E2-related factor 2 (Nrf2) and Hmg CoA reductase degradation 1 (HRD1) in the retina of myotonic dystro-phy (DM) mice. Methods According to random number table method, 150 SD male mice were divided into 5 groups:blank control group (fake model), model control group (DM model), fosinopril group (20 mg·kg-1·d-1 D fosinopril inter-vention), fenofibrate group (400 mg·kg-1·d-1 fenofibrate intervention) and combined group (20 mg·kg-1·d-1 fosinopriland 400 mg·kg-1·d-1 fenofibrate intervention), with 30 in each group. The degree of lens opacity was detected by slit lamp,and the expression of Nrf2 and HRD1 mRNA were detected by real-time fluorescent quantitative PCR; the expression ofNrf2 and HRD1 protein was detected by Western blot, and the TUNEL index of retinal tissue apoptosis were detected bythe TUNEL staining method; the concentration of retinal malonyldialdehyde (MDA) and vascular endothelial growth fac-tor (VEGF), and the activities of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and reactive oxygen spe-cies (ROS) were detected by ELISA; the indicators tested in the five groups of mice were compared. Results There wasno opacity in the control group, and the other four groups of mice had opacity in different degrees, with significant differ-ence among the five groups (P<0.05). There were significant differences in the expression of Nrf2 and HRD1 mRNAand the protein in the five groups (P<0.05). The expression of Nrf2 and HRD1 mRNA in the retina was the highest in theblank control group, followed by the combined group, the single drug group, the model control group from high to low.There were significant differences in TUNEL index of retinal tissue apoptosis among the five groups (P<0.05). The mod-el control group was the highest, followed by the fosinopril group, the fenofibrate group, the combined group and blankcontrol group from high to low. There were significant differences in the expression of MDA, VEGF, GSH-PX, SOD andROS in the lens between the five groups (P<0.05). GSH-PX, SOD activity in the blank control group were the highest,MDA, VEGF concentration, ROS activity were the lowest, followed by the combined group, the single drug group fromlow to high, and then the model control group. Conclusion Fosinopril combined with fenofibrate can effectively increasethe expression of Nrf2 and HRD1 in retina of DM mice to reduce oxidative stress injury and endoplasmic reticulum stresslevels, thereby delaying the DM process and improving the retinal function of diabetic mice
      【Key words】 Retina; Fosinopril; Fenofibrate; Nuclea