天津医药

天津医药 ›› 2016, Vol. 44 ›› Issue (7): 849-852.doi: 10.11958/20150245

• 实验研究 • 上一篇    下一篇

利拉鲁肽对 2 型糖尿病大鼠降血压、利水盐的作用机制探讨

王少清 毛楠 周萍 汪力 高芳 卫怡勋 樊均明 付平   

  1. 1 成都医学院第一附属医院肾病科（邮编 610500）；2西南医科大学附属中医院肾脏内科；3 四川大学华西医院肾脏内科
  • 收稿日期:2015-10-20 修回日期:2016-02-23 出版日期:2016-07-15 发布日期:2016-07-15
  • 通讯作者: 汪力 E-mail:wowosasa2003@163.com
  • 作者简介:王少清（1976）， 男， 副主任医师， 副教授， 博士， 主要从事慢性病肾损害机制及干预研究
  • 基金资助:
    四川省教育厅 2013 年科研资助重点项目（13ZA0213）； 四川省卫生厅 2013 年科研资助项目（130386）； 成都医学院驼鸟计划 2012年专项基金资助项目（CYX12-024）；2014校级大学生创新实验计划项目（CXXS201422）

Liraglutide promotes the reduction of blood pressure and drives the water and salt through in renal medulla of type 2 diabetes rats

WANG Shaoqing1, MAO Nan, ZHOU Ping， WANG Li, GAO Fang1 WEI Yixun, FAN Junming, FU Ping   

  1. 1 Department of Nephrology, the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, China；2 Department of Nephrology, the Affiliated Traditional Medicine Hospital of Southwest Medical University；3 Department of Nephrology, West China Hospital, Sichuan University
  • Received:2015-10-20 Revised:2016-02-23 Published:2016-07-15 Online:2016-07-15
  • Contact: WANG Li E-mail:wowosasa2003@163.com

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摘要： 目的 通过观察胰高血糖素样肽-1（GLP-1）类似物利拉鲁肽对 2 型糖尿病大鼠肾脏内髓一氧化氮合酶（NOS）、环加氧酶 2（COX2）表达的影响， 探讨利拉鲁肽降血压和利水盐的作用机制。 方法 30 只雄性 SD 大鼠给予高糖高脂饲料喂养， 自由摄水， 8 周后空腹注射链脲佐菌素（STZ）， 成功建立 2 型糖尿病大鼠模型 18 只， 选取 12 只随机分为利拉鲁肽处理 2 型糖尿病模型（DMT）组和 2 型糖尿病模型（DM）组， 另取 12 只正常大鼠随机分为利拉鲁肽处理野生型大鼠（WTT）组和野生型大鼠对照（WT）组，每组 6 只。 DMT 和 WTT 组每天予以利拉鲁肽（200 μg/kg 体质量）皮下注射， DM 和 WT 组每天予以等量生理盐水皮下注射， 各组分别在给药后 0、2、4、6 周检测血糖和血压， 给药后 6 周收集尿液检测 K、Na、Cl 离子浓度， 然后处死大鼠， 收集血液检测血 K、Na、Cl 离子浓度， 取肾组织通过 Real-time PCR 和 Western blot 检测肾脏内髓 NOS 和 COX2 的 mRNA 和蛋白表达水平。 结果 利拉鲁肽干预后， DMT 组大鼠血糖（F=5.933， P < 0.05）及血压（F=22.070， P < 0.05）随时间变化逐渐降低。 在干预 6 周后， DMT 组大鼠血糖（mmol/ L： 12.78±3.82 vs. 18.75±1.68）和血压（mmHg： 119.98±4.43 vs. 136.42±4.48）较 DM 组均明显降低（P < 0.05）， 血液中 K、 Na、Cl 离子浓度与 DM 组相比无明显差异， 但尿液中 K（mmol/L： 46.55±6.43 vs. 33.13±9.71）、Na（mmol/L： 56.33±8.83 vs. 41.20±7.25）、Cl（mmol/L： 159.81±25.06 vs. 71.44±12.99）离子浓度高于 DM 组大鼠（P < 0.05）， 且肾脏内髓 NOS、 COX2 的 mRNA 和蛋白表达均高于 DM 组大鼠（P < 0.05）。 结论 利拉鲁肽可能通过 NOS 诱导 COX2 的表达增强，发挥利水盐、降血压的作用。

关键词: 胰高血糖素样肽-1, 利拉鲁肽, 肾脏内髓, 2型糖尿病, 一氧化氮合酶, 环加氧酶2

Abstract: Objective To observe the effects of glucagon like peptide-1 (GLP-1) analogues liraglutide on expressions of nitric oxide synthase (NOS) and cyclo-oxygen-ase (COX)2 in renal medulla of type 2 diabetes rats, and the mechanism of its lowering blood pressure and promoting excretion of water and salt in kidney. Methods Type 2 diabetes model rats were generated by high-fat and high-sugar feeding for 8 weeks followed by intraperitoneal injection of streptozotocin (STZ). Subse⁃ quently, eighteen type 2 diabetes rats were divided into two groups: liraglutide treatment group (DMT) and diabetes group (DM). Twelve normal rats were divided into two groups: liraglutide treatment wild type group (WTT) and wild type group (WT). DMT and WTT groups were given liraglutide (200 μg/kg) by subcutaneous injection, DM and WT groups were given equivalent normal saline by the same way. The levels of blood glucose and blood pressure were detected at 0, 2, 4 and 6 weeks after treatment in groups of rats. Samples of urine were collected for detecting ion concentrations (K +, Na+ and Cl-) af⁃ ter treatment for six weeks. Rats were sacrificed and blood samples were collected for detecting ion concentrations (K +, Na+ and Cl-). The expression levels of NOS and COX2 mRNA and protein in renal medulla were detected by real-time PCR and Western blot assay. Results After treating with liraglutide, the values of blood glucose (F=5.933, P < 0.05) and blood pres⁃sure (F=22.070, P < 0.05) were gradually decreased in DMT group. After treatment with liraglutide for 6 weeks, the values of blood glucose (mmol/L:12.78±3.82 vs. 18.75±1.68) and blood pressure (mmHg:119.98±4.43 vs. 136.42±4.48) were signifi⁃ cantly decreased (P < 0.05) in DMT group than those of DM group (P < 0.05). There were no significant differences in the concentrations of K +, Na + and Cl- between the two groups. There were higher levels of K + (mmol/L:46.55±6.43 vs. 33.13± 9.71), Na+ (mmol/L: 56.33±8.83 vs. 41.20±7.25) and Cl- (mmol/L:159.81±25.06 vs. 71.44±12.99) in urine in DMT group than those of DM group (P < 0.05). The mRNA levels and protein expressions of NOS and COX2 in renal medulla were significant⁃ ly increased in DMT group than those of DM group (P < 0.05). Conclusion GLP-1 analogues liraglutide may enhance the expression of COX2 by increasing the expression of NOS to excrete water and salt, and decrease blood pressure.

Key words: glucagon-like peptide-1, liraglutide, renal medulla, type 2 diabetes, nitricoxide synthase, cyclooxygenase 2