CHIMERIC RENIN-ANGIOTENSIN SYSTEM DEMONSTRATES SUSTAINED INCREASE IN BLOOD-PRESSURE OF TRANSGENIC MICE CARRYING BOTH HUMAN RENIN AND HUMAN ANGIOTENSINOGEN GENES

A reaction between enzyme renin and its only natural substrate angiote nsinogen is the initial and rate-limiting step for producing a potent vasoconstrictor angiotensin II as the final product of the renin-angio tensin system, a contributory factor in the pathogenesis of hypertensi on. In order to assess the role of the interaction of human renin with human angiotensinogen in the development of high blood pressure, we h ave constructed the chimeric renin-angiotensin cascade in mice compris ing both human renin and human angiotensinogen as well as the endogeno us angiotensin-converting enzyme and angiotensin II receptor by cross- mating separate lines of transgenic mice carrying either the human ren in or human angiotensinogen genes. Although each single gene carrier d id not develop hypertension despite the observed normal tissue-specifi c expression of the transgenes, dual gene strains exhibited a chronica lly sustained increase in blood pressure. Administration of a human re nin-specific inhibitor (ES-8891) was effective in reducing the elevate d blood pressure only against the cross-mated hybrid mice, but treatme nt of an angiotensin-converting enzyme inhibitor (captopril) and a sel ective antagonist (DuP 753) directed at the angiotensin II receptor de creased 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 initi ated by the interaction between the products of the two human genes.