Role of proteasome in the development of hypertension

蛋白酶体在高血压发生中的作用

基本信息

批准号：
10672075
负责人：
TAKAOKA Masanori
金额：
$ 1.66万
依托单位：
Osaka University of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672075/
关键词：
proteasome proteasome inhibitor deoxycorticosterone hypertension endothelin ischemic reperfusion injury

项目摘要

To search for a possible role for proteasome in hypertension, we examined the effect of a proteasome inhibitor, N-benzyloxycarbonyl-Ile-Glu-(O-t-Bu)-Ala-leucinal (PSI). Vehicle-treated DOCA-salt rats developed marked hypertension, with an increase in aortic endothelin (ET-1) content. The administration of PSI to DOCA-salt hypertensive rats suppressed the elevation of systolic blood pressure, accompanied by a decrease in aortic ET-1 content. Morphological studies on the rats given the vehicle showed aortic hypertrophy. A significant decrease in vascular wall hypertrophy was observed in the PSI-treated DOCA-salt rats. These results indicate that PSI can prevent the DOCA-salt-induced hypertension and vascular hypertrophy and the effect is accompanied by suppression of ET-1 production in the aorta. We suggest that a proteasome has an important role in the pathogenesis of DOCA-salt hypertension, possibly through the enhancement of ET-1 production in blood vessels.In addition to hypertension … More , ET-1 is considered to participate in the pathogenesis of ischemic acute renal failure (ARF). If proteasome exerts its functions in the renal ET-1 production, PSI would be useful for the treatment of ischemic ARF. Thus, we also examined whether PSI has preventive effects on ischemic ARF in rat models. Our results showed that PSI was capable of preventing renal function impairment as well as renal lesions in ischemic ARF rats, and the effect was accompanied by a decrease in renal ET-1 content. These results suggest that proteasome is involved in the enhanced production of ET-1 in the kidney and the consequent renal functional damage in ischemic ARF.The present study provides evidence that PSI suppresses the increased ET-1 content in the aorta and kidney of DOCA-salt and ischemic ARF rats, respectively. Therefore, proteasome probably plays an essential role in the enhanced production of ET-1. In addition, our findings indicate that the use of proteasome inhibitors may be useful for the treatment of other cardiovascular diseases that results from aberrant ET-1 production. Less

为了寻找蛋白酶体在高血压中的可能作用，我们检查了蛋白酶体抑制剂 N-苄氧基羰基-Ile-Glu-(O-t-Bu)-Ala-亮氨酸 (PSI) 的作用，经载体处理的 DOCA 盐大鼠出现了显着的变化。高血压，主动脉内皮素 (ET-1) 含量增加对 DOCA 盐高血压大鼠施用 PSI 抑制收缩压升高。对给予媒介物的大鼠进行的形态学研究表明，在经过 PSI 处理的 DOCA 盐大鼠中观察到血管壁肥厚显着减少。预防 DOCA 盐诱导的高血压和血管肥大，并且该作用伴随着主动脉中 ET-1 产生的抑制，我们认为蛋白酶体在这一过程中具有重要作用。 DOCA-盐高血压的发病机制可能是通过增强血管中ET-1的产生来实现的。除了高血压之外，如果蛋白酶体发挥其作用，ET-1被认为参与了缺血性急性肾衰竭（ARF）的发病机制。由于 PSI 在肾脏 ET-1 产生中发挥作用，因此可用于治疗缺血性 ARF。因此，我们还研究了 PSI 是否对大鼠模型中的缺血性 ARF 具有预防作用。能够预防缺血性 ARF 大鼠的肾功能损害和肾脏病变，并且该作用伴随着肾脏 ET-1 含量的降低。这些结果表明蛋白酶体参与了肾脏中 ET-1 的增强。本研究提供的证据表明，PSI 分别抑制 DOCA 盐和缺血性 ARF 大鼠主动脉和肾脏中 ET-1 含量的增加。蛋白酶体可能在增加 ET-1 的产生方面发挥着重要作用。此外，我们的研究结果表明，使用蛋白酶体抑制剂可能有助于治疗因 ET-1 产生异常而导致的其他心血管疾病。