A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess
Open Access
- 1 January 2008
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Journal of the American Society of Nephrology
- Vol. 19 (1), 47-58
- https://doi.org/10.1681/asn.2007040401
Abstract
The syndrome of apparent mineralocorticoid excess arises from nonfunctional mutations in 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. Loss of 11betaHSD2 permits glucocorticoids to activate the mineralocorticoid receptor, and the hypertension in the syndrome is presumed to arise from volume expansion secondary to renal sodium retention. An 11betaHSD2 null mouse was generated on an inbred C57BL/6J genetic background, allowing survival to adulthood. 11betaHSD2(-/-) mice had BP approximately 20 mmHg higher on average compared with wild-type mice but were volume contracted, not volume expanded as expected. Initially, impaired sodium excretion associated with increased activity of the epithelial sodium channel was observed. By 80 days of age, however, channel activity was abolished and 11betaHSD2(-/-) mice lost salt. Despite the natriuresis, hypertension remained but was not attributable to intrinsic vascular dysfunction. Instead, urinary catecholamine levels in 11betaHSD2(-/-) mice were double those in wild-type mice, and alpha1-adrenergic receptor blockade rescued the hypertensive phenotype, suggesting that vasoconstriction contributes to the sustained hypertension in this model. In summary, it is proposed that renal sodium retention remains a key event in apparent mineralocorticoid excess but that the accompanying hypertension changes from a renal to a vascular etiology over time.Keywords
This publication has 53 references indexed in Scilit:
- Extrarenal Na+Balance, Volume, and Blood Pressure Homeostasis in Intact and Ovariectomized Deoxycorticosterone-Acetate Salt RatsHypertension, 2006
- Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting SystemJournal of the American Society of Nephrology, 2006
- Hypertension, Kidney, and Transgenics: A Fresh PerspectivePhysiological Reviews, 2006
- Impact of Nedd4 Proteins and Serum and Glucocorticoid-Induced Kinases on Epithelial Na+ Transport in the Distal NephronJournal of the American Society of Nephrology, 2005
- Mechanisms of mineralocorticoid action: determinants of receptor specificity and actions of regulated gene productsTrends in Endocrinology & Metabolism, 2004
- 11β-Hydroxysteroid Dehydrogenase Type 2 in Mouse AortaHypertension, 2003
- RAPID COMMUNICATIONIn vivo inhibition of renal 11β-hydroxysteroid dehydrogenase in the rat stimulates collecting duct sodium reabsorptionClinical Science, 2001
- 11β-Hydroxysteroid dehydrogenase in human vascular cellsKidney International, 2000
- The syndrome of apparent mineralocorticoid excessQJM: An International Journal of Medicine, 1998
- Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion.JCI Insight, 1989