Human hypertension caused by mutations in the kidney isozyme of 11β–hydroxysteroid dehydrogenase

Mune, Tomoatsu; Rogerson, Fraser M.; Nikkila, Heli; Agarwal, Anil K.; White, Perrin C.

doi:10.1038/ng0895-394

Cited by 601 publications

(278 citation statements)

References 45 publications

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“…Apparent mineralocorticoid excess was described as a rare autosomal recessive syndrome that comprises severe childhood hypertension, strokes, volume expansion, hypokalemia, and metabolic alkalosis, all symptoms responsive to aldosterone antagonists, despite the virtual absence of aldosterone in blood plasma (New et al 1977). Based on the obvious similarities with the phenotype of 'licorice intoxication' (phenocopy), Mune and co-workers followed a candidate gene approach, and identified homozygous loss-of-function mutations (Arg208Cys; Arg213Cys) in the renal isoform of HSD11B2 in eight of nine families with AME (Mune et al 1995). Similarly to blocking with glycyrrhetinic acid, the mutated HSD11B2 fails to inactivate cortisol, leaving the MR unprotected.…”

Section: Apparent Mineralocortiocid Excess (Ame)mentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Section: Apparent Mineralocortiocid Excess (Ame)mentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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“…[10][11][12][13][14] The reduced activity of the mutated 11BHSD2 enzyme allows unconverted cortisol to stimulate the mineralocorticoid receptor in the kidney, resulting in early onset of hypertension due to renal sodium retention, hypokalaemic alkalosis, suppression of the renin-angiotensin-aldosterone system and an elevated ratio of cortisol to cortisone metabolites in urine. [10][11][12][13][14] Treatment with aldosterone receptor antagonists, like spironolactone, reverses the condition. 10 Although the clinical picture seem to be typical in the majority of AME patients, a milder form of AME with low-renin hypertension and hypoaldosteronism but normal potassium values and no alkalosis has also been described.…”

Section: Introductionmentioning

confidence: 99%

Association between a variant in the 11β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

et al. 2000

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The enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11BHSD2) converts cortisol to cortisone in the kidney, thereby protecting the mineralocorticoid receptor from the mineralocorticoid actions of cortisol. The syndrome of Apparent Mineralocorticoid Excess (AME), a rare monogenic form of early onset hypertension with autosomal recessive inheritance, is caused by homozygous or compound heterozygous loss of function mutations in the 11BHSD2 gene. Association has been reported between a microsatellite marker flanking the 11BHSD2 gene (D16S496) and primary hypertension. The aim of this study was to identify variants in the 11BHSD2 gene and to test if such variants or the D16S496 are associated with primary hypertension, in Swedes. To address this, the coding sequences of the 11BHSD2 gene was screened for mutations in 20 patients with primary hypertension with single strand conformation polymorphism and direct DNA sequencing techniques. A poly-

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“…[13][14][15] The biological role of 11␤-HSD2 is to provide selective access of aldosterone to the mineralocorticoid receptor (MR) by inactivating cortisol. The absence or inhibition of 11␤-HSD2 results in apparent mineralocorticoid excess with distal tubular sodium retention and potassium loss as a result of promiscuous access of 11␤-hydroxyglucocorticoids to the MR. 12,16,17 Our group has previously shown that bile inhibits 11␤-HSD2 when the enzyme was expressed in COS-I cells. 18 Before the novel theory that sodium retention and potassium loss in cirrhosis is mediated by inhibition of 11␤-HSD2 becomes accepted knowledge, 2 questions must be addressed.…”

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confidence: 99%

Inhibition of 11?-hydroxysteroid dehydrogenase by bile acids in rats with cirrhosis

et al. 1999

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Renal sodium retention and potassium loss occur early, in many instances in the preascitic state of cirrhosis, an observation that cannot be fully explained by increased aldosterone concentrations. We therefore hypothesize that 11␤-hydroxysteroid dehydrogenase 2 (11␤-HSD2), which protects mineralocorticoid receptors (MR) from glucocorticosteroids, is down-regulated in cirrhosis. Cirrhosis was induced by bile duct ligation in rats. The urinary ratio of (tetrahydrocorticosterone ؉ 5␣-tetrahydrocorticosterone)/ 11-dehydro-tetrahydrocorticosterone [(THB؉5␣-THB)/ THA] was measured by gas chromatography. Cortical collecting tubules (CCT) were isolated by microdissection and used for measurements of the activity of 11␤-HSD2 by assessing the conversion of corticosterone to dehydrocorticosterone. The mRNA content of 11␤-HSD2 was determined by reverse-transcription polymerase chain reaction (RT-PCR) in CCTs. The urinary ratio of (THB؉5␣-THB)/ THA increased concomitantly with the urinary excretion of bile acids following bile duct ligation. Chenodeoxycholic acid (CDCA) dose-dependently inhibited 11␤-HSD2 in CCT with a Ki of 19.9 mol/L. Four weeks after bile duct ligation, 11␤-HSD2 activity was decreased in CCT, an observation preceded by a reduced mRNA content at weeks 2 and 3. In cirrhosis, the MR-protecting effect by 11␤-HSD2 is diminished, and therefore, endogenous glucocorticoids can induce MR-mediated sodium retention and potassium loss. (HEPATOLOGY 1999;30:623-629.)Renal sodium retention and potassium loss are observed in patients suffering from cirrhosis. Traditionally, this abnormality was attributed to secondary hyperaldosteronism as a consequence of renal hypoperfusion related to intraabdominal fluid sequestration.

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Human hypertension caused by mutations in the kidney isozyme of 11β–hydroxysteroid dehydrogenase

Cited by 601 publications

References 45 publications

Genetics of arterial hypertension and hypotension

Genetics of arterial hypertension and hypotension

Association between a variant in the 11β-hydroxysteroid dehydrogenase type 2 gene and primary hypertension

Inhibition of 11?-hydroxysteroid dehydrogenase by bile acids in rats with cirrhosis

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