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.