Document Detail

Chimeric renin-angiotensin system demonstrates sustained increase in blood pressure of transgenic mice carrying both human renin and human angiotensinogen genes.
MedLine Citation:
PMID:  8505294     Owner:  NLM     Status:  MEDLINE    
A reaction between enzyme renin and its only natural substrate angiotensinogen is the initial and rate-limiting step for producing a potent vasoconstrictor angiotensin II as the final product of the renin-angiotensin system, a contributory factor in the pathogenesis of hypertension. In order to assess the role of the interaction of human renin with human angiotensinogen in the development of high blood pressure, we have constructed the chimeric renin-angiotensin cascade in mice comprising both human renin and human angiotensinogen as well as the endogenous angiotensin-converting enzyme and angiotensin II receptor by cross-mating separate lines of transgenic mice carrying either the human renin or human angiotensinogen genes. Although each single gene carrier did not develop hypertension despite the observed normal tissue-specific expression of the transgenes, dual gene strains exhibited a chronically sustained increase in blood pressure. Administration of a human renin-specific inhibitor (ES-8891) was effective in reducing the elevated blood pressure only against the cross-mated hybrid mice, but treatment of an angiotensin-converting enzyme inhibitor (captopril) and a selective antagonist (DuP 753) directed at the angiotensin II receptor decreased the basal level of blood pressure even in single gene carriers as well as in dual gene mice. These results clearly demonstrated that the sustained increase in blood pressure of the hybrid mice was initiated by the interaction between the products of the two human genes.
A Fukamizu; K Sugimura; E Takimoto; F Sugiyama; M S Seo; S Takahashi; T Hatae; N Kajiwara; K Yagami; K Murakami
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  268     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  1993 Jun 
Date Detail:
Created Date:  1993-07-07     Completed Date:  1993-07-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  11617-21     Citation Subset:  IM    
Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan.
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MeSH Terms
Angiotensin I / blood
Angiotensin II / blood
Angiotensinogen / blood,  genetics*
Biphenyl Compounds / pharmacology
Blood Pressure* / drug effects
Captopril / pharmacology
Dipeptides / pharmacology
Imidazoles / pharmacology
Mice, Transgenic
Morpholines / pharmacology
Recombinant Proteins / metabolism
Renin / antagonists & inhibitors,  blood,  genetics*
Renin-Angiotensin System / genetics*,  physiology
Tetrazoles / pharmacology
Reg. No./Substance:
0/Biphenyl Compounds; 0/Dipeptides; 0/Imidazoles; 0/Morpholines; 0/Recombinant Proteins; 0/Tetrazoles; 11002-13-4/Angiotensinogen; 11128-99-7/Angiotensin II; 114798-26-4/Losartan; 129445-88-1/ES 8891; 62571-86-2/Captopril; 9041-90-1/Angiotensin I; EC

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