AT1R blocker losartan attenuates intestinal epithelial cell apoptosis in a mouse model of Crohn's disease.
AT1R blocker losartan attenuates intestinal epithelial cell apoptosis in a mouse model of Crohn's disease.
复制标题
AT1R 阻断剂氯沙坦可减弱克罗恩病小鼠模型中的肠上皮细胞凋亡。
DOI：
10.3892/mmr.2015.4686
复制
发表时间：
2016-02
影响因子：
3.4
通讯作者：
Zhao Q
中科院分区：
文献类型：
--
作者：
Liu TJ;Shi YY;Wang EB;Zhu T;Zhao Q
血管紧张素II是肾素-血管紧张素系统的主要效应子，通过血管紧张素II 1型受体（AT 1 R）在肠道炎症中发挥重要作用。本研究旨在探讨AT 1 R阻断剂氯沙坦对2，4，6-三硝基苯磺酸（TNBS）诱导的结肠炎的保护作用。在诱导结肠炎前2周向雄性成年C57 BL/6 J小鼠给予氯沙坦，捕获整个结肠的图像以记录变化，根据显微镜评分系统进行评分，并进行逆转录-定量聚合酶链反应以研究结肠炎症。检测肠上皮屏障通透性，采用末端脱氧核苷酸转移酶缺口末端标记法（TUNEL）检测肠上皮细胞凋亡，采用免疫印迹法检测肠上皮细胞凋亡相关蛋白表达水平。Losartan能够减轻TNBS诱导的体重减轻和结肠损伤。此外，辅助性T细胞1介导的促炎性细胞因子被氯沙坦抑制，肠道通透性在很大程度上得以保留。TUNEL染色显示，在洛沙坦治疗的小鼠中IEC凋亡减少。Losartan还增加了B细胞淋巴瘤2（Bcl-2）/Bcl-2相关X蛋白（Bax）的比例，并抑制caspase-3的诱导。提示AT 1 R阻断剂氯沙坦可能通过抑制肠上皮细胞凋亡而减轻TNBS诱导的结肠炎。氯沙坦的作用部分是通过增加Bcl-2/Bax比值和随后抑制促凋亡介质caspase-3的诱导来介导的。
Angiotensin II, which is the main effector of the renin-angiotensin system, has an important role in intestinal inflammation via the angiotensin II type 1 receptor (AT1R). The present study aimed to investigate the protective effects of the AT1R blocker losartan on 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis. Losartan was administered to male adult C57BL/6 J mice 2 weeks prior to the induction of colitis, and images of the whole colon were captured to record changes, scored according to a microscopic scoring system, and reverse transcription-quantitative polymerase chain reaction were performed in order to investigate colonic inflammation. In addition, intestinal epithelial barrier permeability was evaluated, and intestinal epithelial cell (IEC) apoptosis was measured using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and apoptosis-related protein expression levels were detected by western blotting. Losartan was able to attenuate TNBS-induced body weight loss and colonic damage. Furthermore, T helper 1-mediated proin-flammatory cytokines were suppressed by losartan, and gut permeability was largely preserved. TUNEL staining revealed reduced IEC apoptosis in the losartan-treated mice. Losartan also increased the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio and suppressed caspase-3 induction. These results suggested that the AT1R blocker losartan may attenuate TNBS-induced colitis by inhibiting the apoptosis of IECs. The effects of losartan were partially mediated through increasing the Bcl-2/Bax ratio and subsequently suppressing the induction of the proapoptotic mediator caspase-3.