Hypertensive and hypotensive mice produced by the introduction and disruption of genes on the renin-angiotensin system.
We constructed in mice the chimeric renin-angiotensin cascade comprising human renin, human angiotensinogen, and the endogenous angiotensin-converting enzyme and angiotensin II (A II) receptors by crossmating separate lines of transgenic mice carrying either gene. Although hypertension did not develop in the single-gene carriers despite the observed tissue-specific expression of the transgenes, dual-gene strains exhibited a chronically sustained increase in blood pressure (BP). The systolic BP was 130 +/- 7 mmHg, which is about 30 mmHg higher than that of control mice. Administration of a selective antagonist directed at the A II receptor decreased the basal BP in both single-gene and dual-gene mice. In addition, we generated two lines of knockout mice by homologous recombination in mouse embryonic stem cells. One line consisted of angiotensionogen-deficient mice, which failed to produce angiotensinogen in the liver, resulting in the complete loss of plasma angiotensin 1. The systolic BP of the mice was 66.9 +/- 4.1 mmHg, significantly lower than that of the controls (100.4 +/- 4.4 mmHg). The second line consisted of A II-receptor type la-deficient mice, which also exhibited hypotension (24 mmHg lower than that of controls). These results demonstrated that the renin-angiotensin system plays an indispensable role in maintaining normal BP in vivo, and cannot be replaced by other hormonal and neuronal systems.
Murakami
K
K
Institute of Applied Biochemistry, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan.
Tanimoto
K
K
Sugaya
T
T
Fukamizu
A
A
D000818:Animals; D001794:Blood Pressure / Q000235:genetics*; D018014:Gene Transfer Techniques; D006801:Humans; D006973:Hypertension / Q000235:genetics; D007022:Hypotension / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012084:Renin-Angiotensin System / Q000235:genetics*