| Budget Amount *help |
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
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
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, 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
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