Please wait a minute...
浙江大学学报(医学版)  2019, Vol. 48 Issue (6): 603-608    DOI: 10.3785/j.issn.1008-9292.2019.12.03
原著     
急进高原缺氧对大鼠肝脏孕烷X受体表达的影响
袁雪纯1,2(),向大伟2,敏琼3,丁怡丹1,2,赵安鹏2,王荣1,2,*()
1. 兰州大学药学院, 甘肃 兰州 730000
2. 中国人民解放军联勤保障部队第九四○医院 全军高原医学重点实验室, 甘肃 兰州 730050
3. 甘肃省肿瘤医院药剂科, 甘肃 兰州 730050
Effects of acute hypoxia on expression of pregnane X receptor in liver tissues of rats exposed to high altitude
YUAN Xuechun1,2(),XIANG Dawei2,MIN Qiong3,DING Yidan1,2,ZHAO Anpeng2,WANG Rong1,2,*()
1. College of Pharmacy, Lanzhou University, Lanzhou 730000, China
2. Key Laboratory of the Plateau Medicine, The 940 th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Lanzhou 730050, China
3. Pharmacy Department, Gansu Provincial Cancer Hospital, Lanzhou 730050, China
 全文: PDF(2858 KB)   HTML( 14 )
摘要:

目的: 研究急进高原缺氧环境对大鼠肝脏孕烷X受体(PXR)表达的影响及相关机制。方法: Wistar雄性大鼠40只,随机分为对照组和急进高原缺氧12、24、36、48 h组,每组8只。待预定缺氧时间完成,采集各组大鼠腹主动脉血,全自动血气分析仪进行血气分析;HE染色观察肝组织病理变化状况;实时定量PCR测定各组大鼠肝组织中PXR mRNA水平;蛋白质印迹法测定各组大鼠肝组织中PXR和蛋白酶SUG1的表达。结果: 与对照组比较,急进高原缺氧12 h后大鼠血液酸碱度值降低;缺氧24 h后动脉血氧饱和度(SaO2)低于80%,动脉氧分压(PaO2)低于60 mmHg(1 mmHg=0.133 kPa);缺氧48 h后动脉二氧化碳分压(PaCO2)增加(P < 0.05)。对照组大鼠肝组织结构完整,急进高原缺氧12、24 h组肝组织中央静脉有明显水肿,缺氧36、48 h组大鼠肝组织见炎性浸润。大鼠肝脏内PXR mRNA表达从急进高原缺氧12 h时即显著下调,缺氧12、24、36、48 h组分别降低了63%、96%、86%、85%(均P < 0.05);其蛋白表达从缺氧36 h后显著上调,缺氧36、48 h后分别上调93%、99%(均P < 0.05)。蛋白酶SUG1的表达从缺氧24 h开始降低,缺氧24、36、48 h后分别下降14%、34%、46%(均P < 0.01)。结论: 急进高原缺氧可对大鼠肝脏中核受体PXR表达产生影响,蛋白酶SUG1可能是影响急进高原缺氧下PXR表达的调控因素。

关键词: 高海拔急性病低氧/病理生理学适应, 生理学受体, 胞质和核/生理学大鼠, Wistar    
Abstract:

Objective: To investigate the effects of high-altitude hypoxic environment on the expression of pregnane X receptor (PXR) in rat liver and related mechanism. Methods: Wistar rats were randomly divided into five groups with 8 rats in each group, the rats were exposed to high-plateau hypoxia for 0 (control group), 12, 24, 36 and 48 h, respectively. Abdominal aortic blood samples were collected for blood gas analysis. HE staining was used to observe the pathological changes of liver tissue. The expression levels of PXR mRNA in liver tissues were determined by RT-PCR. Western blot analysis was performed to determine the protein expression of PXR and protease SUG1 in liver tissues of rats. Results: Compared with the control group, the blood pH of the rats decreased after 12 h of acute hypoxia. After 24 h exposed to hypoxia, SaO2 was lower than 80%, PaO2 was lower than 60 mmHg (1 mmHg=0.133 kPa); and PaCO2 increased after 48 h exposed to hypoxia (P < 0.05). There was obvious edema in the central vein of the liver tissue at 12 h and 24 h after exposure to hypoxia. The liver tissue of the rats exposed to hypoxia for 36 h and 48 h showed inflammatory infiltration. The expression of PXR mRNA was significantly decreased by 63%, 96%, 86%, and 85%at 12, 24, 36 h, and 48 h after exposure to hypoxia (all P < 0.05), respectively. The protein expression of PXR was significantly up-regulated by 93%and 99%after 36 h and 48 h exposure to hypoxia (all P < 0.05), respectively. The protein expression of proteinase SUG1 decreased by 14%, 34%and 46%after 24, 36 and 48 h after hypoxia (all P < 0.01). Conclusion: Acute hypoxia at high altitude can affect the expression of nuclear receptor PXR in rat liver, and protease SUG1 may be a regulatory factor for PXR expression in hypoxia.

Key words: Altitude    Acute disease    Hypoxia/physiopathology    Adaptation, physiological    Receptors, cytoplasmic and nuclear/physiology    Liver    Rats, Wistar
收稿日期: 2019-07-24 出版日期: 2020-01-19
:  R594.3  
基金资助: 国家科技重大专项(2018ZX09J18109-001);国家自然科学基金(81673508)
通讯作者: 王荣     E-mail: yxc_ins1997@163.com;wangrong-69@163.com
作者简介: 袁雪纯(1997—), 女, 硕士研究生, 主要从事高原药物代谢酶研究; E-mail:yxc_ins1997@163.com; https://orcid.org/0000-0001-9368-367X
服务  
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章  
袁雪纯
向大伟
敏琼
丁怡丹
赵安鹏
王荣

引用本文:

袁雪纯,向大伟,敏琼,丁怡丹,赵安鹏,王荣. 急进高原缺氧对大鼠肝脏孕烷X受体表达的影响[J]. 浙江大学学报(医学版), 2019, 48(6): 603-608.

YUAN Xuechun,XIANG Dawei,MIN Qiong,DING Yidan,ZHAO Anpeng,WANG Rong. Effects of acute hypoxia on expression of pregnane X receptor in liver tissues of rats exposed to high altitude. J Zhejiang Univ (Med Sci), 2019, 48(6): 603-608.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2019.12.03        http://www.zjujournals.com/med/CN/Y2019/V48/I6/603

组别 n 酸碱度值 SaO2(%) PaO2(mmHg) PaCO2(mmHg)
与对照组比较,*P < 0.05.SaO2:动脉血氧饱和度;PaO2:动脉氧分压;PaCO2:动脉二氧化碳分压.1 mmHg=0.133 kPa.
对照组 8 7.43±0.03 91.28±1.67 60.29±4.83 25.32±3.55
缺氧12 h组 8 7.29±0.10* 84.70±8.91* 61.13±7.95 24.17±2.96
缺氧24 h组 8 7.41±0.04 73.57±8.48* 56.60±4.83 25.75±1.51
缺氧36 h组 8 7.32±0.12* 67.45±5.22* 55.27±5.48 24.28±2.41
缺氧48 h组 8 7.37±0.10 69.43±13.90* 52.43±10.72* 28.49±3.84*
表 1  各组大鼠血气指标比较
图 1  各组大鼠肝组织病理检查结果
图 2  各组大鼠肝脏中PXR mRNA表达量比较(n=8)
图 3  各组大鼠肝脏中PXR和SUG1蛋白表达(n=8)
1 BAHRKE M S , SHUKITT-HALE B . Effects of altitude on mood, behaviour and cognitive functioning. A review[J]. Sports Med, 1993, 16 (2): 97- 125
doi: 10.2165/00007256-199316020-00003
2 BASNYAT B , HOFMEYR R , TOLKEN G et al. Acute high-altitude illness[J]. S Afr Med J, 2017, 107 (7): 556- 561
doi: 10.7196/SAMJ.2017.v107i7.12612
3 李向阳, 刘永年, 袁明 et al. 高原低氧对药物代谢酶CYP2C9和2C19活性及蛋白表达的影响[J]. 药学学报, 2012, 47 (2): 188- 193
LI Xiangyang , LIU Yongnian , YUAN Ming et al. Effect of high altitude hypoxia on the activity and protein expression of CYP2C9 and CYP2C19[J]. Acta Pharmaceutica Sinica, 2012, 47 (2): 188- 193
4 TIEN E S , NEGISHI M . Nuclear receptors CAR and PXR in the regulation of hepatic metabolism[J]. Xenobiotica, 2006, 36 (10-11): 1152- 1163
doi: 10.1080/00498250600861827
5 HARMSEN S , MEIJERMAN I , BEIJNEN J H et al. The role of nuclear receptors in pharmacokinetic drug-drug interactions in oncology[J]. Cancer Treat Rev, 2007, 33 (4): 369- 380
doi: 10.1016/j.ctrv.2007.02.003
6 SMUTNY T , MANI S , PAVEK P . Post-translational and post-transcriptional modifications of pregnane X receptor (PXR) in regulation of the cytochrome P450 superfamily[J]. Curr Drug Metab, 2013, 14 (10): 1059- 1069
doi: 10.2174/1389200214666131211153307
7 MASUYAMA H , INOSHITA H , HIRAMATSU Y et al. Ligands have various potential effects on the degradation of pregnane X receptor by proteasome[J]. Endocrinology, 2002, 143 (1): 55- 61
8 荣黎, 曾维政, 吴晓玲 . 高原缺氧与肝脏损伤[J]. 世界华人消化杂志, 2009, 17 (21): 2171- 2178
RONG Li , ZENG Weizheng , WU Xiaoling . High-altitude hypoxia and liver injury[J]. World Chinese Journal of Digestology, 2009, 17 (21): 2171- 2178
doi: 10.3969/j.issn.1009-3079.2009.21.010
9 TOLSON A H , WANG H . Regulation of drug-metabolizing enzymes by xenobiotic receptors:PXR and CAR[J]. Adv Drug Deliv Rev, 2010, 62 (13): 1238- 1249
doi: 10.1016/j.addr.2010.08.006
10 LEGENDRE C , HORI T , LOYER P et al. Drug-metabolising enzymes are down-regulated by hypoxia in differentiated human hepatoma HepaRG cells:HIF-1alpha involvement in CYP3A4 repression[J]. Eur J Cancer, 2009, 45 (16): 2882- 2892
doi: 10.1016/j.ejca.2009.07.010
[1] 李雪, 李文斌, 封士兰, 王荣. 血红蛋白在高原低氧适应中的机制研究进展[J]. 浙江大学学报(医学版), 2019, 48(6): 674-681.
[2] 张圣,胡振杰,叶璐,郑亚如. 决策树分析在急性心肌梗死事件预测中的应用[J]. 浙江大学学报(医学版), 2019, 48(6): 594-602.
[3] 丁怡丹, 李文斌, 王荣, 张建春. 高原低氧对血脑屏障结构及其药物通透性影响的研究进展[J]. 浙江大学学报(医学版), 2019, 48(6): 668-673.
[4] 张丹丹,王军梅. 胎儿肝血管瘤的产前影像学诊断和管理[J]. 浙江大学学报(医学版), 2019, 48(4): 439-445.
[5] 伦永志,孙杰. 肝细胞癌患者外周血单个核细胞诊断候选基因的筛选及其调控网络分析[J]. 浙江大学学报(医学版), 2019, 48(2): 148-157.
[6] 余钻标,林作栋,郎德海. 经皮机械血栓清除联合支架植入治疗急性髂股静脉血栓形成患者中远期疗效评估[J]. 浙江大学学报(医学版), 2018, 47(6): 623-627.
[7] 尹孝亮,郎德海,王迪. 经皮机械血栓清除治疗急性髂股静脉血栓形成患者疗效观察[J]. 浙江大学学报(医学版), 2018, 47(6): 588-594.
[8] 王星星,王盼盼,杨旭燕. 系统性红斑狼疮合并器官特异性自身免疫性疾病的相关研究进展[J]. 浙江大学学报(医学版), 2018, 47(4): 435-440.
[9] 张美霞 等. 静脉溶栓获益的最大梗死体积阈值与急性缺血性卒中患者发病时间的关系[J]. 浙江大学学报(医学版), 2017, 46(4): 384-389.
[10] 王庆松 等. 基于CT灌注成像的侧支评分预测急性前循环大血管闭塞患者动脉取栓治疗预后的价值[J]. 浙江大学学报(医学版), 2017, 46(4): 377-383.
[11] 柳银兰,罗燕,杨文君,施军平,庄振杰. 甘草酸二铵肠溶胶囊对棕榈酸诱导的肝细胞炎症相关基因表达影响[J]. 浙江大学学报(医学版), 2017, 46(2): 192-197.
[12] 陈刚,张鼎,应亚草,王志峰,陶伟,朱皓,张景峰,彭志毅. 国产载药微球经动脉化疗栓塞治疗不可切除原发性肝癌的临床研究[J]. 浙江大学学报(医学版), 2017, 46(1): 44-51.
[13] 刘芳 等. 瞬时弹性成像技术和声辐射力脉冲成像技术对慢性乙型肝炎肝纤维化的诊断价值[J]. 浙江大学学报(医学版), 2016, 45(4): 416-421.
[14] 陈滟珊 等. 转瓶变速培养对微胶囊肝细胞聚集体形成及活性的影响[J]. 浙江大学学报(医学版), 2016, 45(4): 403-409.
[15] 郎夏冰 等. 中国住院患者急性肾损伤流行病学调查现状[J]. 浙江大学学报(医学版), 2016, 45(2): 208-213.