Published Online
on October 30, 2006

A more recent version of this article appeared on December 1, 2006

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Submitted on March 24, 2006
Revised on April 20, 2006

Disturbed Homeostasis in Sodium-Restricted Mice Heterozygous and Homozygous for Aldosterone Synthase Gene Disruption

Natalia Makhanova; Maria L.S. Sequeira-Lopez; R. Ariel Gomez; Hyung-Suk Kim; and Oliver Smithies^*

From the Departments of Pathology and Laboratory Medicine (N.M., H.-S.K., O.S.) and Pediatrics (M.L.S.S.-L., R.A.G.), University of Virginia, Charlottesville.

^* To whom correspondence should be addressed. E-mail: jenny_langenbach{at}med.unc.edu.

Abstract--We have determined that differences in expression of aldosterone synthase (AS) affect responses to a low-salt diet. In AS-null mice (AS^-/-), but not in wild-type, low salt significantly decreased plasma sodium and increased potassium. The increased urine volume (1.5xwild-type) and decreased urine osmolality (0.7xwild-type), present in AS^-/- mice on normal salt, became more severe (2.3xwild-type and 0.5xwild-type) on low salt, but neither changed in wild-type. In both genotypes, plasma vasopressin was similar on normal and low salt, and desmopressin injection significantly increased urine osmolality. Renal mRNA levels for aquaporin 1 and 3 were unchanged by genotype or diet and epithelial sodium channel and Na⁺-K⁺-2Cl^--cotransporter by genotype. In AS^-/- mice, aquaporin 2 mRNA increased on normal salt, whereas Na⁺Cl^--cotransporter and cortex K⁺ channel mRNAs decreased on both diets. The low blood pressure of AS^-/- mice was decreased further by low salt, despite additional increases in renin, intrarenal arterial wall thickness, and macula densa cyclogenase-2 mRNA. In AS^+/- mice on normal salt, adrenal AS mRNA was slightly decreased (0.7xwild-type), but blood pressure was normal. On low salt, their blood pressure was less than wild-type (101±2 mm Hg versus 106±2 mm Hg), even though renin mRNA increased to 2xwild-type. We conclude that aldosterone is critical for urine concentration and maintenance of blood pressure and even a mild reduction of AS expression makes blood pressure sensitive to low salt, suggesting that genetic differences of AS levels in humans may influence how blood pressure responds to dietary salt.

Key words: aldosterone synthase • blood pressure • electrolytes • renin • COX-2

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