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Mice heterozygote null for 11βHSD2 do not regulate ENaC activity in response to dietary sodium content
Author(s) -
Bailey Matthew A.,
Mullins John J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.735.1
Subject(s) - epithelial sodium channel , endocrinology , medicine , mineralocorticoid receptor , renal sodium reabsorption , amiloride , reabsorption , sodium , chemistry , mineralocorticoid , renal function , excretion , kidney , blood pressure , aldosterone , organic chemistry
Mutations in 11β‐hydroxysteroid dehydrogenase type 2 (11βHSD2) cause Apparent Mineralocorticoid Excess (AME), in which the mineralocorticoid receptor (MR) is inappropriately activated by glucocorticoids. Although AME is rare, milder forms may cause salt‐sensitive hypertension. We have assessed blood pressure (BP) and renal function in 11βHSD2 heterozygous null mice, having ~50% reduction in enzyme activity. Mice (n=7) were maintained on either a standard (0.3%) or high (3%) sodium chow for 3 weeks. Renal clearance experiments were used to measure the effect of amiloride (2mg/kg IV) on sodium excretion. On standard chow BP was ~90mmHg in both groups of mice. Increasing dietary sodium increased BP in 11βHSD2 +/− mice but not in controls (101±2 vs 90±2mmHg; P<0.01). High salt diet increased fractional excretion of sodium in both groups of animals but the response was significantly blunted in 11βHSD2 +/− mice. Whereas sodium loading prompted a down‐regulation of ENaC in control mice, robust amiloride‐sensitive sodium reabsorption was still observed in 11βHSD2 +/− mice. Chronic MR blockade rescued both the blood pressure and renal phenotypes. Thus a reduction in 11βHSD2 activity impairs the ability of the kidney to down‐regulate ENaC‐mediated sodium reabsorption in response to sodium loading and this involves MR‐mediated pathways. These data suggest mild‐loss of function of 11βHSD2 may be clinically significant.