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 mouse 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 +/- 4.1 mm Hg, significantly lower than that of wild-type mice (100.4 +/- 4.4 mm Hg). This profound hypotension in angiotensinogen-deficient mice demonstrates an indispensable role for the renin-angiotensin system in maintaining blood pressure.