Salt-Sensitive Blood Pressure in Mice With Increased Expression of Aldosterone Synthase

Abstract

Abstract-To study the effects of modestly increased expression of aldosterone synthase (AS), we generated mice (AS hi/hi ) by replacing the 3Ј 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 Ϸ10-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 ␣ 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. Key Words: aldosterone synthase Ⅲ blood pressure Ⅲ dietary salt Ⅲ renin-angiotensin-aldosterone system Ⅲ water metabolism A n increasing body of data indicates that genetic susceptibility to essential hypertension is determined by small changes in many genes 1 rather by large changes in a few genes. 2 As a result, it is very difficult to establish a causative link between inherited differences in a candidate gene when studying human population, even when a strong correlation can be demonstrated. One approach to establish causation is to create differences in a candidate gene in mice and to ask whether blood pressure (BP) or other relevant parameters change. Here, we use this approach to determine the effect of modest increase in the expression of the gene cyp11b2, coding for aldosterone synthase (AS).Recent studies show that Ϸ10% of patients with essential hypertension have a high ratio of plasma aldosterone/plasma renin activity, suggesting some degree of inappropriately increased production of aldosterone. 3,4 Aldosterone plays an important role in controlling electrolyte homeostasis and BP, but it also has newly recognized effects in the remodeling of the heart, in abnormal vascular endothelial function, and in renal injury. 5 AS catalyzes the last step of aldosterone synthesis, and several investigators have published data suggesting that variations in the human AS gene (CYP11B2) may contrib...

Depressor effect of chymase inhibitor in mice with high salt-induced moderate hypertension

“…In the present study, male WT mice were given a HS load (2% NaCl) in their drinking water for 12 wk. There was no significant increase of blood pressure during the first week, consistent with previous reports showing that short-term HS intake does not cause hypertension in mice (30,49). However, a significant increase of blood pressure was observed from week 2, and it persisted until week 12.…”

“…Previous studies have shown that circulating levels of ANG II, aldosterone, and renin (activity or concentration) were all significantly decreased by short-term salt intake in rats (19,44), whereas chronic salt loading increased circulating ANG II, aldosterone, and PRA in the present study, causing hypertension in normotensive mice by RAS activation. In contrast to our present observations, several studies (30,49) have found that mice fed a HS diet (8% salt) for up to 4 wk showed no significant change of blood pressure despite consuming ϳ200 mg salt/day (calculated on the basis of daily food intake). The difference from our results may have several explanations, including a higher salt intake in our study (500 vs. 200 mg/day) and a longer salt loading period (12 vs. 4 wk).…”

“…In previous rodent models, it has been observed that a short-term increase of dietary salt intake does not elevate blood pressure (30,36), although that addition of other manipulations, such as deoxycorticosterone (41) or ANG II (25), can consistently produce salt-sensitive hypertension. However, no previous study has assessed the impact of prolonged HS loading in WT mice.…”

Long-term effects of adrenalectomy or spironolactone on blood pressure control and regression of left ventricle hypertrophy in patients with primary aldosteronism

“…Experimental animal studies have proposed that the excess of aldosterone can induce extracellular matrix and collagen deposition, 31 especially in the presence of high dietary salt intake. 32 Stimulation of fibroblast proliferation and collagen synthesis might be related to the activation of mineralocorticoid receptors in human cardiomyocytes, inducing inflammatory process and specific ionic movements, modulated also by the interaction with the angiotensin, bradykinin and endothelin systems. 10,33 The demonstration of a regression of LV mass after specific treatment would provide additional evidence of the causal role of aldosterone-mediated excessive activation of mineralocorticoid receptors in the development of LV hypertrophy.…”

Effect of endothelial microRNAs on blood pressure homeostasis

“…Previous studies demonstrated that a high salt diet (8% NaCl) did not affect blood pressure homeostasis in different strains of either male or female mice such as C57BL/6, 129 and NZW/LacJ [25][26][27] . On the other hand, it has been shown that high salt containing water (2% NaCl) intake induced significant elevation of BP and HR two weeks after loading in C57BL/6 male mice 10) .…”