中国血液净化

中国血液净化 ›› 2016, Vol. 15 ›› Issue (04): 235-240.doi: 10.3969/j.issn.1671-4091.2016.04.011

• 基础研究 • 上一篇    下一篇

尾加压素II在Dahl盐抵抗大鼠血压调节中的作用及机制研究

吴菲,张爱华   

  1. 1北京大学第三医院肾内科
  • 收稿日期:2016-01-05 修回日期:2016-02-15 出版日期:2016-04-12 发布日期:2016-04-19
  • 通讯作者: 张爱华 zhangaihua0982@sina.com E-mail:zhangaihua0982@sina.com
  • 基金资助:

    国家自然基金委项目资助(项目编号81170706,81341022,81570663)

Roles of urotensin II in the regulation of blood pressure in Dah1 salt resistant rat

  • Received:2016-01-05 Revised:2016-02-15 Online:2016-04-12 Published:2016-04-19

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摘要： 目的我们既往在容量超负荷而血压维持正常的腹膜透析患者中，发现血浆尾加压素Ⅱ(urotensin Ⅱ，UⅡ)水平升高，提示UⅡ在这类患者的血压调节中发挥作用，但其调节机制未明。本研究选取与容量超负荷而血压维持正常的特性相类似的Dahl 盐抵抗大鼠模型，研究其在高盐负荷下血压调节，循环及肾脏的UII 表达，探讨UⅡ在Dahl 盐抵抗(dahl salt-resistant，SR)大鼠血压调节中的作用及机制。方法Dahl 盐敏感(dahl salt-sensitive，SS)和SR 大鼠，UII 受体敲除的小鼠及C57BL/6 野生型小鼠，高盐负荷6～8 周，检测基线及高盐负荷6～8 周后血压，血浆UII，尿UII，肾脏及主动脉的UII 及UII 受体的mRNA 及蛋白的表达，24h 尿钠排泄，24h 肌酐清除率。结果①高盐负荷6 周后SS 大鼠血压显著高于SR 大鼠[(160±13)mmHg 比(114±6)mmHg,t=8.191,P＜0.001]；SR 大鼠血浆UII 水平显著高于SS 大鼠[(60.3±3.8)pg/ml 比(51.6±13.5)pg/ml,t=2.450,P=0.021]。高盐负荷4 周后SR 大鼠尿UII 的浓度显著高于SS 大鼠[(236.90±27.89)ng/g 比(114.70±6.28ng/g, t= 3.898, P=0.003)]，24h尿钠排泄量[4 周时：(3.243±0.306)mmol 比(1.753±0.127)mmol，t=3.942，P=0.010]；6 周时：(2.870±0.134)mmol 比(1.713 ± 0.077)mmol，t=3.942，P＜0.001] 和6w 时肌酐清除率亦显著升高[(6.532 ±0.269)ml/min 比(2.632±0.172)ml/min，t=12.210，P＜0.001]。②高盐负荷6w 后，SR 大鼠的肾脏UII 受体(现称为UT)的蛋白表达明显高于SS 大鼠[(0.059±0.008)比(0.036±0.001),t=4.540,P=0.010]，UII及受体的表达主要位于肾小管上皮细胞③在高盐饮食后第4 周，UII 受体敲除的小鼠收缩压显著高于野生普通型小鼠[(113±3)mmHg 比(102±4)mmHg，t=4.750,P=0.003]，而第4 周24h 尿钠排泄量[(3.11±0.60)μmol 比(4.29±0.68)μmol，t=-2.785,P=0.036]及第2 周肌酐清除率显著降低[(0.23±0.02)ml/min 比(0.11±0.01)ml/min，t=3.018,P=0.016]。结论本研究首次证实UII 在高盐负荷后盐抵抗大鼠的血压调节中发挥作用，机制可能与UII对小动脉舒张作用及促进肾小管上皮细胞对钠的排泄有关。

关键词: 尾加压素Ⅱ, 高血压, 盐敏感, 盐抵抗, 尾加压素Ⅱ受体基因敲除

Abstract: Objective Our previous study suggests that urotensin II (UII) plays a role in vasodilation when fluid volume in the body increases. To elucidate the role of UII in blood pressure regulation, we conducted this study using animal models that resemble the hemodynamic profiles of volume resistant and volume sensitive patients. In addition, a UII receptor knockout mouse model was established. Methods Dahl salt resistant (SR) rats, Dah1 salt sensitivity (SS) rats, wild type (WT) mice, and UII receptor knock out (KO) mice were used in this study. After placing these four groups of animals on a high salt diet for 6 or 8 weeks, renal
tissue was used to perform immunochemistry staining, real time PCR, and western blot to measure UII level in kidney. Results After high salt diet for 6 weeks, systolic blood pressure was significantly higher in SS group than in SR group (160±13 mmHg vs. 114±6 mmHg, t=8.191, P＜0.001). Compared with SS rats, SR
rats had higher plasma UII (60.3±3.8 vs. 51.6±13.5 pg/ml, t=2.450, P=0.021), urinary UII (236.9±27.89 ng/g vs. 114.70 ± 6.28 ng/g, t=3.898, P=0.003), 24 hours urinary sodium excretion (4w: 3.243 ± 0.306 mmol vs. 1.753±0.127 mmol, t=3.942, P=0.010; 6w: 2.870±0.134 mmol vs. 1.713±0.077 mmol, t=3.942, P＜0.001),
and urinary creatinine clearance (6w: 6.532±0.269 ml/min vs. 2.632±0.172 ml/min, t=12.210, P＜0.001). After high salt diet for 6 weeks, more UII receptor was expressed in renal tubular epithelia of SR rats as compared with those of SS rats (0.059±0.008 vs. 0.036±0.001, t=4.540, P=0.010). After high salt diet for 8 weeks, systolic blood pressure was significantly higher in KO mice than in WT mice (113 ± 3 mmHg vs. 102 ± 4mmHg, t=4.750, P=0.003). Conclusions The present results first demonstrate that UII can play a role in the regulation of blood pressure in Dah1 SR rats, probably through the effects of UII on ateriole dilatation and promotion of sodium excretion from renal tubules.

Key words: Urotensin II, Dahl salt-sensitive rat, Dahl salt-resistant rat, volume resistance-hypertension, UII receptor knock-out