Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene

Stewart, Paul M.; Gupta, Amrit; Sheppard, M. C.; Whorwood, C. B.; Howie, Alexander J.; Milford, David V.; Krozowski, Zygmunt

doi:10.1016/s0140-6736(96)90211-1

Cited by 234 publications

(107 citation statements)

References 21 publications

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…Our data suggest reduced 11b-HSD2 activity, both in children with end-stage renal failure and in patients after renal transplantation having steroid-free immunosuppressive therapy. For CRF children, these results are in line with those from other groups demonstrating reduced activity of 11b-HSD2 in adults with chronic renal failure (6,28,29). There was no difference in the cortisol/cortisone ratios between patients suffering from chronic renal failure and the pediatric renal allograft recipients in this study.…”

Section: Discussionsupporting

confidence: 91%

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

Schroth¹,

Plank²,

Rauh³

et al. 2006

eur j endocrinol

View full text Add to dashboard Cite

Objective: The conversion of cortisol (F) to cortisone (E) is catalyzed by 11beta-hydroxysteroid dehydrogenase type 2 (11b-HSD2). Children suffering from chronic renal failure (CRF) have a decreased activity of 11b-HSD2 contributing to increased arterial blood pressure. The objective was to investigate whether a normal conversion of F to E is achieved after renal transplantation (TX) in children. Methods: Fifteen children with CRF, 17 children with steroid-free immunosuppression after TX, and 18 healthy controls (CO) were enrolled. The activity of 11b-HSD2 in plasma was calculated using the ratio of F/E determined by tandem mass spectrometry, the ratio of tetrahydrocortisol (THF) þ 5a-tetrahydrocortisol (5aTHF) in urine determined by gas chromatography/mass spectrometry, and the ratio of (THF þ 5aTHF)/tetrahydrocortisone (THE) in urine determined by tandem mass spectrometry. Results: The F/E ratio (mean^S.D./S.E.M.) was significantly higher in CRF and TX (5.6^1.9/0.6, 7.12^3.1/0.9) than in CO (1.18^0.2/0.03, P , 0.0001) groups. The (THF þ 5aTHF)/THE ratio in CRF (1.19^1.1/0.5) and TX (1.19^0.1/0.5) groups was significantly higher than in controls (0.21^0.05/0.18, P , 0.0001). Positive correlations between plasma and urinary ratios (P ¼ 0.0004. R 2 ¼ 0.73 in CRF, P ¼ 0.0013, R 2 ¼ 0.56 in TX, P , 0.0001, R 2 ¼ 0.66 in CO) were found, whereas significant correlations between F/E or (THF þ 5aTHF)/THE ratios and blood pressure, the number of antihypertensive drugs taken or creatinine clearance could not be found. Conclusions: In all children with chronic renal failure plasma and urinary cortisol/cortisone ratios are elevated and do not return to normal levels after renal allograft transplantation. This suggests that renal transplantation does not normalize 11b-HSD2 activity.European Journal of Endocrinology 154 555-561

show abstract

Section: Discussionsupporting

confidence: 91%

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

Schroth¹,

Plank²,

Rauh³

et al. 2006

eur j endocrinol

View full text Add to dashboard Cite

show abstract

“…12,17,21,[44][45][46][47] All 3 mechanisms leading to such a reduced activity of 11␤-HSD2 can be diagnosed by an increased urinary ratio of (tetrahydrocortisol ϩ allotetrahydrocortisol)/tetrahydrocortisone in humans 32,46 or (tetrahydrocorticosterone ϩ 5␣-tetrahydrocorticosterone)/11-dehydrotetrahydrocorticosterone in rats. 21 For instance, these ratios increase by about 50% to 100% when glycyrrhetinic acid, 46 the model compound for inhibiting 11␤-HSD is given, an inhibition that causes sodium retention with hypertension. In the present investigation, we showed for the first time that the ratio of (THBϩ5␣-THB)/THA increased by about 100% during the development of cirrhosis, indicating biologically significantly enhanced access of 11␤-hydroxyglucocorticosteroids to the MR.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1999

View full text Add to dashboard Cite

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.

show abstract

“…[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

View full text Add to dashboard Cite

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-

show abstract

Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene

Cited by 234 publications

References 21 publications

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

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

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

Contact Info

Product

Resources

About