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.
Institute of Applied Biochemistry, Tsukuba Advanced Research Alliance, University of Tsukuba, Japan.
K
K
Murakami
K
K
Tanimoto
T
T
Sugaya
A
A
Fukamizu
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*