2002 Fiscal Year Final Research Report Summary
Role of cytochrome P450 dependent elcosanoids in progressive renal diseases and hypertension
| Project/Area Number |
12671018
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Kidney internal medicine
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| Research Institution | Miyagi University of Education |
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Principal Investigator |
OMATA Ken Miyagi University of Education, Health Administration Center, Director, 保健管理センター, 教授 (50194634)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Sadayoshi Tohoku University School of Medicine, The Second Department ofInteraal Medicine, Professor, 大学院・医学系研究科, 教授 (40271613)
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| Project Period (FY) |
2000 – 2002
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| Keywords | cytochrome P450 / arachidonic acid / 20-HETE / EET / SHR / androgen / hypertension / progressive renal disease |
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| Research Abstract |
The kidney plays a key role in the development and the maintenance of hypertension. We studied the pathophysiological role of renal vasoactive substances. Renin-angiotensin, kallikrein-kinin, prostaglandins and cytochrome P450 systems are localized to specific nephron segments, suggesting the intimate relationship between these substances and the nephron segments in which that localized. There were marked age-dependent changes in the production rate of these substances. The changes are also dependent on the maturation and the differentiation of the nephron. Furthermore, there were significant changes of production rates of these substances in the animal model of hypertension, such as spontaneously hypertensive rats and Dahl salt sensitive rats. The production rate of vasodepressoi substances, such as kallikrein-kinin and prostaglandins systems decreased in hypertensive subjects. On the contrary, the production rate of 19-hydroxyeicosatetraenoic acid (HETE) and 20-HETE which synthesized by renal cytochrome P450, the third metabolic pathway of arachidonic acid increased in hypertensive subjects. 19-HETE stimulates Na-K-ATPase and 20-HETE constricts the vasculature, suggesting the basopressor roles of these substances. In addition, prostacyclin synthesized by cyclooxygenase inhibits and epoxyeicosatrienoic acids synthesized by cytochrome P450 stimulate the cell growth of vascular smooth muscle cells and glomerular mesangial cells in culture. When arachidonic acid is synthesized by cyclooxygenase, the cell growth is inhibited and when arachidonate is synthesize by cytochiome P450, the cell growth is stimulated. Furthermore, androgen stimulates P450 4A protein and 20-HETE production in SHR, In hypertensive subjects prostacyclm, the cyclooxygenase products is decreased and cytochrome P450 activity is increased. These results suggest that these vasoactive substances have the role of the development of renal damage as well as the vascular damage in hypertensive subjects.
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