| Project/Area Number |
06404016
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Applied molecular and cellular biology
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| Research Institution | UNIVERSITY OF TSUKUBA |
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Principal Investigator |
MURAKAMI Kazuo University of Tsukuba, Institute of Applied Biochemistry, Professor, 応用生物化学系, 教授 (70110517)
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| Co-Investigator(Kenkyū-buntansha) |
NOMURA Tatuji Laboratory Animal Research Center, Director, 所長 (10072399)
SUGIYAMA Fumihiro University of Tsukuba, Basic Medicine, Assistant Prof., 基礎医学系, 講師 (90226481)
FUKAMIZU Akiyoshi University of Tsukuba, Institute of Applied Biochemistry, Associate Prof., 応用生物化学系, 助教授 (60199172)
MIYAZAKI Hitoshi University of Tsukuba, Institute of Applied Biochemistry, Associate Prof., 応用生物化学系, 助教授 (40183636)
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| Project Period (FY) |
1994 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥29,100,000 (Direct Cost: ¥29,100,000)
Fiscal Year 1996: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1995: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1994: ¥18,800,000 (Direct Cost: ¥18,800,000)
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| Keywords | renin / angiotensinogen / angiotensin II / angiotensin-receptor / knock out mice / transgenic mice / Hypotensin / Hypertension induced by pregnancy / つくば高血圧マウス / つくば低血圧マウス / アンギオテンシンノーゲン遺伝子 / レニン・アンギオテンシン系 / ジーンターゲテイング法 / アンギオテンシンII受容体欠損マウス / アンギオテンシノーゲン遺伝子 / アンギオテンシンI |
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| Research Abstract |
The important research results in this project are summarized in the fololowing two sections.
(1) Angiotensinogen-Deficient Mice with Hypotension
The renin-angiotensin system is an enzymatic cascade that produces a potent vasoconstrictor octapeptide angiotensin II,through its physiologically inactive intermediate decapeptide angiotensin I,from their precursor angiotensinogen. In the present study, we generated angiotensinogen-deficient mice by homologous recombination in mouses embryonic stem cells. These mice do not produce angiotensinogen in the liver, resulting in the complete loss of plasma immunoreactive angiotensin I.The systolic blood pressure of the homozygous mutant mice was 66.9 <plus-minus> 4.1 mmHg, significantly lower than that of wild-type mice (100.4 <plus-minus> 44 mmHg). This profound hypotension in angiotensinogen-deficient mice demonstrates an indispensable role for the renin-angiotensin system in maintaining blood press
(2) Hypertension Induced in Pregnant Mice by Placental Renin and Maternal Angiotensinogen
Maternal hypertension is a common complication of pregnancy and its pathophysiology is poorly understood. This phenomenon was studied in an animal model by mating transgenic mice expressing components of the human renin-angiotensin system. When transgenic females expressing angiotensinogen were mated with transgenic males expressing renin, the pregnant females displayd a transient elevation of blood pressure in late pregnancy, due to secretion of placental human renin into the maternal circulation. Blood pressure returned to normal levels after delivery of the pups. Histopathologic examination revealed uniform enlargement of glomeruli associated with an increase in urinary protein excretion, myocardial hypertrophy, and necrosis and edema in the placenta. These mice may provide molecular insights into pregnancy-associated hypertension in humans.
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