诱导型一氧化氮合酶对肾血管性高血压及HO-1表达的影响
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摘要
目的：研究诱导型一氧化氮合酶/一氧化氮系统对肾血管性高血压大鼠主动脉血红素加氧酶-1表达的调节作用，以探讨诱导型一氧化氮合酶/一氧化氮与血红素加氧酶-1在肾血管性高血压时二者之间的关系及对肾血管性高血压的影响。
方法：将32只SD大鼠随机分为4组，假手术+生理盐水组(Sham+NaCl组)、假手术+氨基胍组(Sham+AG组)、肾动脉狭窄+生理盐水组(RH+NaCl组)以及肾动脉狭窄+氨基胍组(RH+AG组)，每组8只，以两肾一夹(肾动脉不全结扎)的方式复制肾血管性高血压模型，然后以诱导型一氧化氮合酶特异性抑制剂氨基胍为工具试剂给实验组动物(包括假手术组和肾动脉狭窄组)腹腔注射150mg/kg，每日二次。观察血压的变化，并以酶法测定尿液中一氧化氮终产物NO_2~-／NO_3~-(UNOx)的生成、以逆转录聚合酶链反应(RT-PCR)法测定主动脉血红素加氧酶-1的mRNA表达以及用Western blot法测定主动脉血红素加氧酶-1的蛋白表达水平。
结果：SD大鼠两肾一夹术后，RH+NaCl组动脉血压持续上升，术后第4周时达132.7±6.1mmHg，与术前相比，呈显著升高(P＜0.01)，同时各时间点相应的血压均显著高于Sham+NaCl组；术后第四周RH+AG组的血压为142.8±1.9mmHg远大于RH+NaCl组(p＜0.01)；在Sham+NaCl组和Sham+AG组术后四周血压分别为107.9±1.9mmHg和105.0±1.9mmHg，较术前相比无显著差异，同时二组各时间点相应的血压之间无显著差别。RH+NaCl组尿中UNOx水平肾动脉狭窄术后，显著升高，术后1周由术前的9.76±2.91μmol/24h增加到21.98±3.30μmol/24h。氨基胍能够明显抑制一氧化氮的生成，RH+AG组术后四周UNOx为16.17±5.85μmol/24h，明显低于RH+NaCl组28.54±8.21μmol/24h的水平(P＜0.01)，而对假手术组大鼠的UNOx没有影响。RT-PCR显示术后4周肾动脉狭窄组主动脉血红素加氧酶-1的mRNA表达明显较假手术组高，而RH+AG组血红素加氧酶-1mRNA的表达明显低于RH+NaCl组的水平，但高于假手术组的水平。Western蛋白印迹显示，RH+NaCl组的血红素加氧酶-1蛋白表达明显高于Sham+NaCl组的水平，而氨基胍能够明显抑制肾动脉狭窄引起的血红素加氧酶-1的蛋白表达。对假手术组没有观察到血红素加氧酶-1蛋白的变化。
结论：1．肾血管性高血压时iNOS／NO系统激活，NO生成量增加，对血压具
有重要的调节作用。2．诱导型一氧化氮合酶抑制剂氨基弧能够明显放大肾血管
性高血压的升压效应。3．肾血管性高血压时，血红素加氧酶1的基因及蛋白水平
表达增加，可能是血压调节的重要组成部分。4．肾血管性高血压时iNOS／NO系
统可能对血红素加氧酶＊的表达产生重要的调节作用，iNOS／NO系统产牛的NO
可能是刺激肾血管性高血压时血红素加氧酶l基因及蛋白水平表达增加的重要
因素。
Objective: The goal of this study is to clarify the relationship between inducible nitric oxide synthase/nitric oxide (iNOS/NO) pathway and heme oxygenase-1 expression in renovascular hypertension.
Methods: Thirty-two Spraugue Dawley (SD) rats were randomly divided into four groups: Sham+NaCl group (n=8), Sham+ aminoguanidin (Sham+AG) group (n=8), renovascular hypertension+NaCl (RH+ NaCl) group (n=8) and renovascular hypertension+aminoguanidin (RH+AG) group (n=8). The renovascular hypertension was induced by renal artiery stenosis. Aminoguanidin (AG), the specific inhibitor of inducible nitric oxide synthase, was used in control groups (including Sham and RH group). AG was administrated intraperitoneally at a dose of 150mg/kg two times a day. The arterial pressure was monitored and the NO2- /NO3- (UNOx ) , heme oxygenase-1 mRNA and protein were assayed by Greiss reaction, reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively.
Results: The arterial pressure of rats in RH+ NaCl group increased significantly. Four weeks after operation, it increased to 132.±3.1mmHg from 104.1 ±3.7mmHg before operation. The hypertensive effect of renal artery stenosis was greatly amplified by co-administration of AG In the group of RH+AG, the arterial pressure was 142.8+ 1.9mmHg 4 weeks after operation, which was significantly higher than that in RH+ NaCl group, but Sham+AG and Sham+NaCl groups had no hemodynamic response to AG. In RH+ NaCl group, UNOx, an index of the NO production of the whole body, increased significantly, for example, 1 week after operation (P<0.01), it increased to 21.98?.30|imol/24h from 9.76?.91 |imol/24h before operation. The aminoguanidin obviously inhibited the production of NO. In the
group of RH+AG, the UNOx was 16.17±5.85 μmol/24h in 4 weeks after operation, which was significantly lower than 28.54±8.21 μmol/24h, the UNOx produced by control group (RH+ NaCl group). However, the AG had not effect on the Sham group.
In RH+NaCl and RH+AG groups, the expression of heme oxygenase-1 mRNA in aorta was upregulated significantly, compared with Sham groups'. RT-PCR showed HO-1 mRNA expression in RH+AG group was lower than that in RH+NaCl group,
but higher than that in Sham groups. Western blot demonstrated HO-1 protein increased obviously in RH+NaCl group compared with RH+AG group. AG markedly suppressed HO-1 protein expression that caused by renal artery stenosis, but AG did not change the HO-1 protein expression in Sham group.
Conclusions: 1. iNOS/NO pathway is activated by renovascular hypertension. 2.The hypertensive effect of renal artery stenosis is greatly amplified by co-administration of AG 3. Renovascular hypertension upregulate the expression of HO-1 mRNA and protein. It may play an important role in regulation of arterial pressure. 4.HO-1 is activated and regulated in renovascular hypertension by iNOS/NO pathway.
方法：将32只SD大鼠随机分为4组，假手术+生理盐水组(Sham+NaCl组)、假手术+氨基胍组(Sham+AG组)、肾动脉狭窄+生理盐水组(RH+NaCl组)以及肾动脉狭窄+氨基胍组(RH+AG组)，每组8只，以两肾一夹(肾动脉不全结扎)的方式复制肾血管性高血压模型，然后以诱导型一氧化氮合酶特异性抑制剂氨基胍为工具试剂给实验组动物(包括假手术组和肾动脉狭窄组)腹腔注射150mg/kg，每日二次。观察血压的变化，并以酶法测定尿液中一氧化氮终产物NO_2~-／NO_3~-(UNOx)的生成、以逆转录聚合酶链反应(RT-PCR)法测定主动脉血红素加氧酶-1的mRNA表达以及用Western blot法测定主动脉血红素加氧酶-1的蛋白表达水平。
结果：SD大鼠两肾一夹术后，RH+NaCl组动脉血压持续上升，术后第4周时达132.7±6.1mmHg，与术前相比，呈显著升高(P＜0.01)，同时各时间点相应的血压均显著高于Sham+NaCl组；术后第四周RH+AG组的血压为142.8±1.9mmHg远大于RH+NaCl组(p＜0.01)；在Sham+NaCl组和Sham+AG组术后四周血压分别为107.9±1.9mmHg和105.0±1.9mmHg，较术前相比无显著差异，同时二组各时间点相应的血压之间无显著差别。RH+NaCl组尿中UNOx水平肾动脉狭窄术后，显著升高，术后1周由术前的9.76±2.91μmol/24h增加到21.98±3.30μmol/24h。氨基胍能够明显抑制一氧化氮的生成，RH+AG组术后四周UNOx为16.17±5.85μmol/24h，明显低于RH+NaCl组28.54±8.21μmol/24h的水平(P＜0.01)，而对假手术组大鼠的UNOx没有影响。RT-PCR显示术后4周肾动脉狭窄组主动脉血红素加氧酶-1的mRNA表达明显较假手术组高，而RH+AG组血红素加氧酶-1mRNA的表达明显低于RH+NaCl组的水平，但高于假手术组的水平。Western蛋白印迹显示，RH+NaCl组的血红素加氧酶-1蛋白表达明显高于Sham+NaCl组的水平，而氨基胍能够明显抑制肾动脉狭窄引起的血红素加氧酶-1的蛋白表达。对假手术组没有观察到血红素加氧酶-1蛋白的变化。
结论：1．肾血管性高血压时iNOS／NO系统激活，NO生成量增加，对血压具
有重要的调节作用。2．诱导型一氧化氮合酶抑制剂氨基弧能够明显放大肾血管
性高血压的升压效应。3．肾血管性高血压时，血红素加氧酶1的基因及蛋白水平
表达增加，可能是血压调节的重要组成部分。4．肾血管性高血压时iNOS／NO系
统可能对血红素加氧酶＊的表达产生重要的调节作用，iNOS／NO系统产牛的NO
可能是刺激肾血管性高血压时血红素加氧酶l基因及蛋白水平表达增加的重要
因素。
Objective: The goal of this study is to clarify the relationship between inducible nitric oxide synthase/nitric oxide (iNOS/NO) pathway and heme oxygenase-1 expression in renovascular hypertension.
Methods: Thirty-two Spraugue Dawley (SD) rats were randomly divided into four groups: Sham+NaCl group (n=8), Sham+ aminoguanidin (Sham+AG) group (n=8), renovascular hypertension+NaCl (RH+ NaCl) group (n=8) and renovascular hypertension+aminoguanidin (RH+AG) group (n=8). The renovascular hypertension was induced by renal artiery stenosis. Aminoguanidin (AG), the specific inhibitor of inducible nitric oxide synthase, was used in control groups (including Sham and RH group). AG was administrated intraperitoneally at a dose of 150mg/kg two times a day. The arterial pressure was monitored and the NO2- /NO3- (UNOx ) , heme oxygenase-1 mRNA and protein were assayed by Greiss reaction, reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively.
Results: The arterial pressure of rats in RH+ NaCl group increased significantly. Four weeks after operation, it increased to 132.±3.1mmHg from 104.1 ±3.7mmHg before operation. The hypertensive effect of renal artery stenosis was greatly amplified by co-administration of AG In the group of RH+AG, the arterial pressure was 142.8+ 1.9mmHg 4 weeks after operation, which was significantly higher than that in RH+ NaCl group, but Sham+AG and Sham+NaCl groups had no hemodynamic response to AG. In RH+ NaCl group, UNOx, an index of the NO production of the whole body, increased significantly, for example, 1 week after operation (P<0.01), it increased to 21.98?.30|imol/24h from 9.76?.91 |imol/24h before operation. The aminoguanidin obviously inhibited the production of NO. In the
group of RH+AG, the UNOx was 16.17±5.85 μmol/24h in 4 weeks after operation, which was significantly lower than 28.54±8.21 μmol/24h, the UNOx produced by control group (RH+ NaCl group). However, the AG had not effect on the Sham group.
In RH+NaCl and RH+AG groups, the expression of heme oxygenase-1 mRNA in aorta was upregulated significantly, compared with Sham groups'. RT-PCR showed HO-1 mRNA expression in RH+AG group was lower than that in RH+NaCl group,
but higher than that in Sham groups. Western blot demonstrated HO-1 protein increased obviously in RH+NaCl group compared with RH+AG group. AG markedly suppressed HO-1 protein expression that caused by renal artery stenosis, but AG did not change the HO-1 protein expression in Sham group.
Conclusions: 1. iNOS/NO pathway is activated by renovascular hypertension. 2.The hypertensive effect of renal artery stenosis is greatly amplified by co-administration of AG 3. Renovascular hypertension upregulate the expression of HO-1 mRNA and protein. It may play an important role in regulation of arterial pressure. 4.HO-1 is activated and regulated in renovascular hypertension by iNOS/NO pathway.
引文
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