A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess

Abstract

The syndrome of apparent mineralocorticoid excess arises from nonfunctional mutations in 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. Loss of 11␤HSD2 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 11␤HSD2 null mouse was generated on an inbred C57BL/6J genetic background, allowing survival to adulthood. 11␤HSD2 Ϫ/Ϫ 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 11␤HSD2 Ϫ/Ϫ mice lost salt. Despite the natriuresis, hypertension remained but was not attributable to intrinsic vascular dysfunction. Instead, urinary catecholamine levels in 11␤HSD2 Ϫ/Ϫ mice were double those in wild-type mice, and ␣1-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. In 90% of hypertensive patients, the causal pathophysiology cannot be defined and, in 25%, BP fails to fall to target values with existing therapies. Improved understanding of pathogenesis is key to addressing this problem. Fundamental principles of BP homeostasis have been established through investigation of the rare Mendelian hypertensive disorders. These disorders result almost exclusively from mutations in genes encoding proteins influencing directly or indirectly sodium balance, 1 suggesting that altered renal salt homeostasis is a key factor in the misregulation of BP 2 The fine-tuning of sodium balance is achieved in the distal nephron, determined principally by the actions of aldosterone at the mineralocorticoid receptor (MR). In vitro, MR can be activated with equal potency by both mineralocorticoids and glucocorticoids. 3 In vivo, ligand access is determined by the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2), which catalyzes the rapid conversion of the active glucocorticoid cortisol (corticosterone in mice) to inert cortisone (11-dehydrocorticosterone), thereby

Uninephrectomy reduces 11β-hydroxysteroid dehydrogenase type 1 and type 2 concomitantly with an increase in blood pressure in rats

“…Inhibition of 11b-HSD2 by carbenoxolone was shown to enhance the heart rate in rats (Zhang et al 2006). Furthermore, urinary catecholamine levels were double in 11b-Hsd2 K/K mice (Bailey et al 2008). Thus, the increased blood pressure following UNX might be the consequence of both an enhanced renal sodium retention and an increased sympathetic drive, a hypothesis of interest as it is conceivable that the dampened renal efferent nerve activity to the contralateral kidney after UNX modulates the 11b-HSD activity in the remaining kidney (Recordati et al 2000).…”

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

“…30,31 NCC activity is regulated by several neurohormonal systems, including the sympathetic nerves,angiotensin II, glucocorticoids, sex steroids, vasopressin, and insulin. 32 There is controversy regarding the influence of mineralocorticoids, the dominant regulators of chronic Na + balance.…”

“…We therefore concentrated our studies on mice at 60 days of age, reasoning that any process contributing to DCT hypertrophy remained active at this age and that previous work had confirmed that hypertension in our model is largely driven by renal Na + retention at this age. 31 Increased Total and Phosphorylated NCC in the Plasma Membrane Immunoblotting of whole-kidney homogenates was used to estimate the abundance of NCC and of the specific phosphorylated forms of NCC that are associated with NaCl transport activity. Total NCC and the phosphorylated forms pT53, pT58, and pS71 were more abundant in Hsd11b2 2/2 kidneys than in the wild types ( Figure 4A).…”

“…This paradigm of corticosteroid signaling enjoys robust empirical support in the CNT and CCD. ENaC expression/activity increases when 11bHSD2 is inhibited by pharmacologic 38,39 or genetic 31 means, as a result of MR activation by glucocorticoids.…”

“…We can only speculate that Na + transport in the DCT of Hsd11b2 2/2 mice might be limited by pathologic structural remodeling, resulting in an epithelium that is not adapted for efficient solute transport. Abnormalities are found in subcellular (binucleation, nuclear hyperchromasia, and apical blebbing 31 ) and tissue structure (multiple layers of cells on a single basement membrane; Figure 1). Our data show that NCC phosphorylation status does not always correlate with a wholeorgan measure of transport activity.…”