Genotype-Phenotype Correlations of Mutations and Polymorphisms in HSD11B2, the Gene Encoding the Kidney Isozyme of 11β-Hydroxysteroid Dehydrogenase

Pc, White; Agarwal, AK; Nunez, B. Scott; Giacchetti, Gilberta; Mantero, Franco; Stewart, PM

doi:10.3109/07435800009048598

Cited by 25 publications

(18 citation statements)

References 5 publications

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“…Results of studies using cells transfected with the cDNA encoding the defective 11␤HSD2 of patients with AME have been puzzling. There was small, but measurable 11␤HSD2 activity in the intact cells, but no activity in homogenates (39). The mutations in these patients might not only produce enzymes that are less effective but may also promote the formation of inactive dimers that are more apparent when cells are homogenized.…”

Section: Discussionmentioning

confidence: 99%

Regulation of 11β-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol

Gómez-Sánchez¹,

Ganjam²,

Chen³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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The 11β-hydroxysteroid dehydrogenase (11βHSD) type 1 (11βHSD1) enzyme is an NADP+-dependent oxidoreductase, usually reductase, of major glucocorticoids. The NAD+-dependent type 2 (11βHSD2) enzyme is an oxidase that inactivates cortisol and corticosterone, conferring extrinsic specificity of the mineralocorticoid receptor for aldosterone. We reported that addition of a reducing agent to renal homogenates results in the monomerization of 11βHSD2 dimers and a significant increase in NAD+-dependent corticosterone conversion. Estrogenic effects on expression, dimerization, and activity of the kidney 11βHSD1 and -2 enzymes are described herein. Renal 11βHSD1 mRNA and protein expressions were decreased to very low levels by estradiol (E2) treatment of both intact and castrated male rats; testosterone had no effect. NADP+-dependent enzymatic activity of renal homogenates from E2-treated rats measured under nonreducing conditions was less than that of homogenates from intact animals. Addition of 10 mM DTT to aliquots from these same homogenates abrogated the difference in NADP+-dependent activity between E2-treated and control rats. In contrast, 11βHSD2 mRNA and protein expressions were significantly increased by E2 treatment. There was a marked increase in the number of juxtamedullary proximal tubules stained by the antibody against 11βHSD2 after the administration of E2. Notwithstanding, neither the total corticosterone and 11-dehydrocorticosterone excreted in the urine nor their ratio differed between E2- and vehicle-treated rats. NAD+-dependent enzymatic activity in the absence or presence of a reducing agent demonstrated that the increase in 11βHSD2 protein was not associated with an increase in in vitro activity unless the dimers were reduced to monomers.

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Section: Discussionmentioning

confidence: 99%

Regulation of 11β-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol

Gómez-Sánchez¹,

Ganjam²,

Chen³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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“…A homozygous mutation in Arg279 (399), predicted to lie on the surface of 11␤-HSD2 (429), reduces V max but has little effect on substrate affinity, causing the milder "type II" AME, probably due to minor structural disruption. Overall, AME patients show clear relationships between loss of 11␤-HSD2 activity and phenotype (491,765).…”

Section: Structure and Mutationsmentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

734

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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“…The type 2 enzyme has been shown to be involved in the "protection" of the mineralocorticoid receptor in peripheral tissues (such as distal renal tubules) against occupation by cortisol, exemplified by 11␤-HSD2 gene defects leading to the "apparent mineralocorticoid excess syndrome" (9,10). The physiological role of the type 1 form is less clear, but several studies established a critical role of 11␤-HSD1 in the tissuespecific activation of corticosteroid ligands (11)(12)(13)(14).…”

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confidence: 99%

Comparative Enzymology of 11β-Hydroxysteroid Dehydrogenase Type 1 from Glucocorticoid Resistant (Guinea Pig) Versus Sensitive (Human) Species

Shafqat¹,

Elleby²,

Svensson³

et al. 2003

Journal of Biological Chemistry

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Type 1 11␤-hydroxysteroid dehydrogenase constitutes a prereceptor control mechanism through its ability to reduce dehydroglucocorticoids to the receptor ligands cortisol and corticosterone in vivo. We compared kinetic characteristics of the human and guinea pig 11␤-hydroxysteroid dehydrogenase isozymes derived from species differing in glucocorticoid sensitivity. Both orthologs were successfully expressed as full-length enzymes in yeast and COS7 cells and as soluble transmembrane-deleted constructs in Escherichia coli. Both isozymes display Michaelis-Menten kinetics in intact cells and homogenates and show low apparent micromolar K m values in homogenates, which are lowered by approximately one order of magnitude in intact cells, allowing corticosteroid activation at physiological glucocorticoid levels. Recombinant soluble proteins were expressed and purified with high specific dehydrogenase and reductase activities, revealing several hundredfold higher specificity constants than those reported earlier for the purified native enzyme. Importantly, these purified soluble enzymes also display a hyperbolic dependence of reaction velocity versus substrate concentration in 11-oxoreduction with K m values of 0.8 M (human) and 0.6 M (guinea pig), close to the values obtained from intact cells. Active site titration was carried out with the human enzyme using a novel inhibitor compound and reveals a fraction of 40 -50% active sites/ mol total enzyme. The kinetic data obtained argue against the involvement of 11␤-hydroxysteroid dehydrogenase as a modulating factor for the glucocorticoid resistance observed in guinea pigs. Instead, the expression of 11␤-hydroxysteroid dehydrogenase type 1 in the Zona glomerulosa of the guinea pig adrenal gland suggests a role of this enzyme in mineralocorticoid synthesis in this hypercortisolic species.

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Genotype-Phenotype Correlations of Mutations and Polymorphisms in HSD11B2, the Gene Encoding the Kidney Isozyme of 11β-Hydroxysteroid Dehydrogenase

Cited by 25 publications

References 5 publications

Regulation of 11β-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol

Regulation of 11β-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Comparative Enzymology of 11β-Hydroxysteroid Dehydrogenase Type 1 from Glucocorticoid Resistant (Guinea Pig) Versus Sensitive (Human) Species

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