二甲双胍通过Nrf2/HO-1/NQO1通路减轻子痫前期大鼠胎盘组织氧化应激损伤-现代医学

二甲双胍通过Nrf2/HO-1/NQO1通路减轻子痫前期大鼠胎盘组织氧化应激损伤

单位：1. 宜宾市第二人民医院产科, 四川宜宾 644000;
2. 宜宾市第二人民医院急诊科, 四川宜宾 644000

分类号：R285.5;R714.24

出版年·卷·期（页码）：2022·50·第五期（597-603）

摘要：

目的：研究二甲双胍通过核因子E2相关因子2（Nrf2）/血红素加氧酶-1（HO-1）/磷酸酰胺腺嘌呤二核苷酸醌氧化还原酶1（NQO1）通路减轻子痫前期（PE）大鼠胎盘组织氧化应激损伤的作用。方法：孕鼠随机分为对照组、模型组、二甲双胍组（150 mg·kg^-1）、ML385组（Nrf2/HO-1通路抑制剂，剂量20 mg·kg^-1）、二甲双胍+ML385组（剂量分别为150 mg·kg^-1、20 mg·kg^-1）5组，每组12只，除对照组外，其余组通过皮下注射N-硝基-L-精氨酸甲酯（L-NAME）的方法建立PE大鼠模型。按照分组以药物处理后，测定各组大鼠妊娠晚期血压及24 h尿蛋白含量；检测各组大鼠妊娠结局情况，比较其平均子代数目及体重；测定各组大鼠胎盘组织氧化应激因子谷胱甘肽过氧化物酶（GSH-Px）、丙二醛（MDA）和外周血炎症因子肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、干扰素-γ（IFN-γ）水平；检测各组大鼠胎盘组织Nrf2/HO-1/NQO1通路蛋白表达。结果：与对照组相比，模型组大鼠妊娠晚期平均动脉压、24 h尿蛋白含量、胎盘组织MDA水平及外周血炎症因子TNF-α、IL-6、IFN-γ水平明显升高（P<0.05），胎盘组织GSH-Px水平、平均子代数目及体重、Nrf2、HO-1、NQO1蛋白表达明显降低（P<0.05）。与模型组相比，二甲双胍组大鼠妊娠晚期平均动脉压、24 h尿蛋白含量、胎盘组织MDA水平及外周血炎症因子TNF-α、IL-6、IFN-γ水平降低（P<0.05），平均子代数目及体重、胎盘组织GSH-Px水平、Nrf2、HO-1、NQO1蛋白表达升高（P<0.05）；ML385组大鼠妊娠晚期平均动脉压、24 h尿蛋白含量、胎盘组织MDA水平及外周血炎症因子TNF-α、IL-6、IFN-γ水平升高（P<0.05），平均子代数目及体重、胎盘组织GSH-Px水平、Nrf2、HO-1、NQO1蛋白表达降低（P<0.05）。与二甲双胍+ML385组相比，二甲双胍组大鼠妊娠晚期平均动脉压、24 h尿蛋白含量、胎盘组织MDA水平及外周血炎症因子TNF-α、IL-6及IFN-γ水平降低（P<0.05），平均子代数目及体重、胎盘组织GSH-Px水平、Nrf2、HO-1、NQO1蛋白表达升高（P<0.05）；ML385组大鼠妊娠晚期平均动脉压、24 h尿蛋白含量、胎盘组织MDA水平及外周血炎症因子TNF-α、IL-6及IFN-γ水平升高（P<0.05），平均子代数目及体重、胎盘组织GSH-Px水平、Nrf2、HO-1、NQO1蛋白表达降低（P<0.05）。结论：二甲双胍可激活Nrf2/HO-1/NQO1通路，进而降低PE大鼠血压，减轻胎盘组织氧化应激和炎症损伤，改善其妊娠后期高血压及蛋白尿症状，促使子代存活。

Objective:To study the effect of metformin on reducing the oxidative stress damage of placenta tissue in preeclampsia(PE) rats through nuclear factor erythroid-2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/phosphoamide adenine dinucleotide quinone oxidoreductase 1(NQO1) pathway. Methods:Pregnant rats were randomly divided into model group, metformin(150 mg·kg^-1) group, ML385(Nrf2/HO-1 pathway inhibitor, 20 mg·kg^-1) group, metformin+ML385 group(150 mg·kg^-1, 20 mg·kg^-1) respectively with 12 in each group. Except the control group, other groups were injected subcutaneously with N-nitro-L-arginine methyl ester(L-NAME) to establish PE rat model. After treatment in accordance with the drugs given in each group, the blood pressure and 24-hour urine protein content of rats in each group were measured in the third trimester of pregnancy. The pregnancy outcome of rats in each group was detected and average number and weight of their offspring were compared; the oxidative stress factors of glutathione peroxidase(GSH-Px), malondialdehyde(MDA) and peripheral blood inflammatory factors of tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) and interferon-γ(IFN-γ) levels were determined in each group.The expression of Nrf2/HO-1/NQO1 pathway protein in placenta tissue of rats in each group was detected. Results:Compared with the control group, the mean arterial pressure, 24-hour urine protein content, MDA level in placenta tissue, TNF-α, IL-6 and IFN-γ levels in peripheral blood in the model group increased significantly in the third trimester of pregnancy(P<0.05); the GSH-Px level in placenta tissue, the average number and weight of offspring, the Nrf2, HO-1, and NQO1 proteins expression were reduced significantly(P<0.05). Compared with the model group, the mean arterial pressure, 24-hour urine protein content, MDA level in placenta tissue, and TNF-α, IL-6 and IFN-γ levels in peripheral blood in the metformin group decreased in the third trimester of pregnancy(P<0.05), while the average number and weight of offspring, the GSH-Px level in placenta tissue, the Nrf2, HO-1, and NQO1 proteins expression increased(P<0.05); the mean arterial pressure, 24-hour urine protein content, MDA level in placenta tissue, and TNF-α, IL-6 and IFN-γ levels in peripheral blood in the ML385 group increased in the third trimester of pregnancy(P<0.05), while the average number and weight of offspring, the GSH-Px level in placental tissue, the Nrf2, HO-1, and NQO1 proteins expression decreased(P<0.05). Compared with the metformin+ML385 group, the mean arterial pressure, 24-hour urine protein content, MDA level in placenta tissue, and TNF-α, IL-6 and IFN-γ levels in peripheral blood in the metformin group reduced in the third trimester of pregnancy(P<0.05), while the average number and weight of offspring, the GSH-Px level in placental tissue, and the Nrf2, HO-1, and NQO1 proteins expression increased(P<0.05); the mean arterial pressure, 24-hour urine protein content, MDA level in placenta tissue, and TNF-α, IL-6 and IFN-γ levels in peripheral blood in the ML385 group increased in the third trimester of pregnancy(P<0.05), while the average number and weight of offspring, the GSH-Px level in placental tissue, the Nrf2, HO-1, and NQO1 proteins expression decreased(P<0.05). Conclusion:Metformin can activate the Nrf2/HO-1/NQO1 pathway, thereby lowering the blood pressure of PE rats, reducing the oxidative stress and inflammatory damage of the placenta tissue, improving the symptoms of hypertension and proteinuria in late pregnancy, and promoting the survival of the offspring.

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