Salt-sensitive blood pressure in mice with increased expression of aldosterone synthase.
To study the effects of modestly increased expression of aldosterone synthase (AS), we generated mice (AS(hi/hi)) by replacing the 3' untranslated region of AS mRNA with that from a stable mRNA. AS(hi/hi) mice on a normal-salt diet had 1.5 times the wild-type AS mRNA in adrenals, although their blood pressure and plasma aldosterone did not differ from wild-type mice. Changes in dietary salt did not affect the blood pressure of wild-type mice, but AS(hi/hi) mice had approximately 10-mm Hg higher blood pressure on a high-salt diet than on a low-salt diet and than wild-type mice on either diet. The AS(hi/hi) mice on a high-salt diet also had higher plasma aldosterone, lower plasma potassium, and greater renal expression of the alpha subunit of epithelial sodium channel compared with wild-type mice. The AS(hi/hi) mice on a high-salt diet also had more water intake and urine volume and less urine osmolality than wild-type mice. On a low-salt diet, AS(hi/hi) mice maintained normal blood pressure with less activation of the renin-angiotensin-aldosterone system than wild-type mice. The AS(hi/hi) mice also had less water intake and urine volume and higher urine osmolality than wild-type mice. On a medium high-salt diet, AS(hi/hi) mice were more susceptible than wild-type mice to infusion of angiotensin II, having a higher blood pressure, greater cardiac hypertrophy, and increased oxidative stress. Thus, a modest increase in AS expression makes blood pressure more sensitive to salt, suggesting that genetically increased AS expression in humans may contribute to hypertension and cardiovascular complications in societies with high-salt diets.
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525, USA.
Natalia
N
Makhanova
John
J
Hagaman
Hyung-Suk
HS
Kim
Oliver
O
Smithies
D000450:Aldosterone / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006929:Hyperaldosteronism / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000201:enzymology* / Q000209:etiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D012982:Sodium, Dietary / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D012333:RNA, Messenger; D012982:Sodium, Dietary; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D009569:Nitric Oxide; D000450:Aldosterone; D012964:Sodium; D019405:Cytochrome P-450 CYP11B2; D012083:Renin