Objective: To study the effect of benazepril on the expression of nuclear factor E2 related factor 2 (Nrf2), nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and reactive oxygen species (ROS) concentration in rats with hepatic fibrosis and to explore the possible antifibrotic mechanism of benazepril. Methods: Twenty-two healthy male Sprague-Dawley rats were randomly divided into 3 groups: control group (6 rats), model group (8 rats) and benazepril treatment group (8 rats). Two rats died during modeling and treatment in the model group and the benazepril treatment group, and a model of hepatic fibrosis induced by carbon tetrachloride (CCL(4)) was established. The rats in benazepril group were given benazepril for 8 weeks by gastric gavage. The assessment of liver tissue damage in each group was measured using conventional hematoxylin-eosin and Masson staining. The mRNA level of Nrf2, NOX4 in liver tissue was detected by RT-PCR, and serum ROS concentration was determined by colorimetry. All data were expressed in mean ± standard deviations, and were analyzed using SPSS21.0 statistical software. The data were compared using one-way analysis of variance, and the LSD-t method was used for pairwise comparison between the two groups. The correlation analysis was performed by Spearman's correlation analysis. Results: In the liver of the model group, with the aggravation of liver fibrosis the expression of Nrf2mRNA, NOX4 mRNA and ROS concentration were higher than control group [(4.01 ± 3.40), (31.78 ± 3.96), (1.82 ± 0.46) μg/ ml vs. (0.12 ± 0.11), (2.03 ± 0.31), (1.56±0.84) μg/ml, P < 0.05]. After benazepril treatment, NOX4 mRNA expression and ROS concentration were decreased than the model group [(15.93 ± 5.01), (0.78 ± 0.44) μg/ml vs. (31.78 ± 3.96), (1.82 ± 0.46) μg /ml, P < 0.05], while Nrf2 mRNA expression was higher than the model group [(6.69 ± 4.86) vs. (4.01 ± 3.40), P < 0.05]. There was a positive correlation between Nrf2 and NOX4, Nrf2 and ROS, and NOX4 and ROS (r = 0.616, 0.411, 0.802, P < 0.05). Conclusion: Benazepril may exert an anti-hepatic fibrosis effect by activating Nrf2 expression, or may inhibit the ROS-mediated oxidative stress in response to NOX4.
目的： 研究贝那普利对肝纤维化大鼠肝脏核因子E2相关因子2（Nrf2）、还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶4（NOX4）表达及血清活性氧簇（ROS）浓度的影响，探讨贝那普利可能的抗纤维化机制。 方法： 将22只清洁级健康雄性SD大鼠随机分3组，其中对照组6只，模型组和贝那普利治疗组每组8只，在造模及治疗过程中模型组和贝拉普利治疗组各有2只大鼠死亡，建立四氯化碳诱导的肝纤维化模型，贝那普利治疗组同时应用贝那普利灌胃，共8周，各组肝组织损伤的评估采用常规苏木精-伊红和Masson染色，RT-PCR检测肝组织中Nrf2 mRNA及NOX4 mRNA的表达量、比色法测定血清ROS浓度。所有数据表示为均数±标准差，采用SPSS21.0统计软件分析。计量资料组间比较采用单因素方差分析，两两比较采用LSD-t法；相关性分析采用Spearman相关分析。 结果： 随着肝纤维化的加重，模型组肝脏Nrf2 mRNA、NOX4 mRNA表达及血清ROS浓度均较对照组升高[（4.01±3.40）、（31.78±3.96）、（1.82±0.46）μg/ml对比（0.12±0.11）、（2.03±0.31）、（1.56±0.84）μg/ml，P值均<0.05]。贝那普利治疗后NOX4 mRNA表达和ROS浓度较模型组下降[（15.93±5.01）、（0.78±0.44）μg/ml对比（31.78±3.96）、（1.82±0.46）μg/ml，P值均<0.05]，而Nrf2 mRNA表达较模型组升高（相对表达量6.69±4.86对比4.01±3.40，P < 0.05）。Nrf2与NOX4、Nrf2与ROS、NOX4与ROS三组之间均呈正相关（r值分别为0.616、0.411、0.802，P值均< 0.05）。 结论： 贝那普利可能通过激活Nrf2表达发挥抗肝纤维化作用，亦可能抑制NOX4产生的ROS介导的氧化应激反应，发挥抗肝纤维化作用。.
Keywords: Benazepril; Liver fibrosis; Nicotinamide adenine dinucleotide phosphate oxidase 4; Nuclear factor E2 related factor 2; Reactive oxygen species.