| Project/Area Number |
16570122
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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 |
Functional biochemistry
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| Research Institution | Keio University |
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Principal Investigator |
MUKAI Kuniaki Keio University, School of Medicine, Instructor, 医学部, 助手 (80229913)
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| Co-Investigator(Kenkyū-buntansha) |
MITANI Fumiko Keio University, School of Medicine, Assistant Professor, 医学部, 専任講師 (60041852)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | steroid hormone / mineralocorticoid / aldosterone / glucocorticoid / aldosterone synthase / mineralocorticid receptor |
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| Research Abstract |
Aldosterone is a most potent mineralocorticoid which regulates water and electrolyte metabolisms in mammals. This steroid hormone is synthesized and secreted from the zona glomerulosa of adrenal cortex, and acts through mineralocorticoid receptor (MR) in the epithelial cells transport water and electrolytes. Recently, however, evidence that aldosterone is synthesized in the cardiovascular systems and acts in a paracrine manner through MR has been reported. It has been known that aldosterone is involved in cardiac hypertrophy and fibrosis and in homeostasis of vasculature. In this study, we examined molecular basis for synthesis and action of aldosterone in the cardiovascular systems. Examination of mRNA level of aldosterone synthase in aortas and hearts of normal rats showed that it was detectable but almost at its detection limit. mRNAs of factors responsible for aldosterone action were easily detectable. Next, we employed Dahl salt-sensitive rats fed on 8% NaCl-containing diets as an
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animal model for aldosterone-inducible heart failure. Salt-loading resulted in induction of aldosterone synthase mRNA frequently, while expression levels of the factors for aldosterone action mostly did not changed. Interestingly, expression of a newly cloned factor AZ-1, whose expression correlates with aldosterone synthesis and action, was enhanced in aortas and hearts significantly. Furthermore, we used another experimental animal model of cardiac hypertrophy and fibrosis by continuous administration (6 weeks) of aldosterone into normal rats fed on 1% NaCl-containing drinking water. The aldosterone administration caused hypertension with systolic blood pressure at 170 mmHg. Judging from histochemical analysis of the hearts they showed hypertrophy with accumulating collagenous fibrils. Immunohistochemical examination with anti-AZ-1 antibody revealed that AZ-1 became detectable in capillaries and interstitial spaces between cardiac muscle cells. Aldosterone caused cardiac hypertrophy and fibrosis through MR and induced expression of extracellular matrix proteins including AZ-1. Less
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