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

Gómez-Sánchez, Elise P.; Ganjam, Venkataseshu K.; Chen, Yuan Jian; Liu, Ying; Zhou, Ming; Toroslu, Cigdem; Romero, Damián G.; Hughson, Michael D.; Rodríguez, Ángela de la Hoz; Gómez-Sánchez, Celso E.

doi:10.1152/ajpendo.00409.2002

Cited by 51 publications

(42 citation statements)

References 48 publications

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“…Corticosterone/11-dehydrocorticosterone ratios in rat urine were reported to be about three to four according to ELISA (13) or 0.7 according to a radioimmunoassay (36a), compared with about one to two in the present study.…”

Section: Discussioncontrasting

confidence: 48%

Renal interstitial corticosterone and 11-dehydrocorticosterone in conscious rats

Usa¹,

Singh²,

Netzel³

et al. 2007

American Journal of Physiology-Renal Physiology

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cies in the conversion between active and inactive glucocorticoids in the kidney can lead to hypertension. However, the significance of glucocorticoid metabolism in specific kidney regions in vivo is not clear, possibly in part due to the difficulty in measuring glucocorticoid levels in kidney regions in vivo. We used microdialysis techniques to sample renal interstitial fluid from conscious rats. The levels of corticosterone (active) and 11-dehydrocorticosterone (inactive) were analyzed by liquid chromatography-tandem mass spectrometry. Direct infusion of the 11␤-hydroxysteroid dehydrogenase (11␤-HSD) inhibitor carbenoxolone into the renal medulla induced hypertension, and significantly increased corticosterone levels and the corticosterone/ 11-dehydrocorticosterone ratio, an index of 11␤-HSD activity, in the renal medullary microdialysate, but not in urine or the plasma. Further characterization of conscious, untreated rats (n ϭ 13-16) indicated that corticosterone concentrations (ng/ml) were 0.8 Ϯ 0.1, 1.0 Ϯ 0.1, 66.7 Ϯ 8.1, and 7.9 Ϯ 1.1 in cortical microdialysate, medullary microdialysate, the plasma, and urine, respectively. The corticosterone/11-dehydrocorticosterone ratios were 0.8 Ϯ 0.1, 0.6 Ϯ 0.1, 10.6 Ϯ 1.4, and 1.7 Ϯ 0.1, respectively, in these 4 types of sample. The expression level of 11␤-HSD1 was higher in the medulla than in the cortex, whereas 11␤-HSD2 was most enriched in the outer medulla. Microdialysate levels of corticosterone were ϳ1.6-fold higher in afternoons than in mornings, whereas plasma levels differed by 2.8-fold. These results demonstrated that corticosterone excess in the renal medulla might be sufficient to cause hypertension and provided the first characterization of renal interstitial glucocorticoids.hypertension; 11␤-hydroxysteroid dehydrogenase; microdialysis; mass spectrometry THE BIOLOGICAL ACTIVITY OF glucocorticoids in target organ systems is controlled not only by circulating levels of glucocorticoids but also by intracellular metabolism in target tissue. The metabolism of glucocorticoids in target tissue involves several enzymatic reactions including the interconversion between active and inactive glucocorticoids catalyzed by 11␤-hydroxysteroid dehydrogenases (11␤-HSD) (7, 41). The type 2 isoform of the enzyme, 11␤-HSD2, converts active glucocorticoids, mainly cortisol in human and corticosterone in rodents, to inactive forms, cortisone in human and 11-dehydrocorticosterone in rodents. The type 1 isoform of the enzyme, 11␤-HSD1, has both dehydrogenase and reductase activities but may act predominantly as a reductase in vivo, regenerating biologically active glucocorticoids from their inactive forms (40).Local metabolism of glucocorticoids has particular relevance to renal function. Aldosterone is a powerful and important regulator of electrolyte transport in the distal nephron. Mineralocorticoid receptors in the distal nephron, however, can bind aldosterone and glucocorticoids with nearly equal affinity. 11␤-HSD2 in the distal nephron inactivates glucocorticoids and all...

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Section: Discussioncontrasting

confidence: 48%

Renal interstitial corticosterone and 11-dehydrocorticosterone in conscious rats

Usa¹,

Singh²,

Netzel³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…However, DHEA metabolites may affect GC fate in other organs, since DHEA feeding was shown to decrease 11βHSD1 gene expression in rat liver [32] and to reduce 11βHSD1 activity in human myoblasts [32]. In addition, estradiol decreased 11βHSD1 mRNA and protein in rat kidney to undetectable levels, but yet decreased the NADP + -dependent conversion of CS to DHC by less than 50% [34]. In spontaneously hypertensive rats, DHEA-sulfate enhanced activity of 11βHSD2 in kidney, diminished 11βHSD1 action in liver and therefore increased the ratio of DHC/CS in plasma [35].…”

Section: Discussionmentioning

confidence: 99%

Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: Nuclear and microsomal 11β-hydroxysteroid dehydrogenases

Robinzon

Prough

2005

Archives of Biochemistry and Biophysics

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The 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) activates glucocorticoids (GC) by reversibly converting 11-keto-GC to 11-hydroxy-GC, while 11βHSD2 and 11βHSD3 only catalyzes the reverse reaction. Recently, rat and human 11βHSDs were shown to interconvert 7α-and 7β-hydroxy-dehydroepiandrosterone (7α-or 7β-OH-DHEA) with 7-oxo-DHEA. We report that pig kidney microsomes (PKMc) and nuclei (PKN) oxidize 7α-OH-DHEA to 7-oxo-DHEA at higher rates with NAD + , than with NADP + . Corticosterone (CS), dehydrocoticosterone (DHC), 11α-and 11β-hydroxyprogesterone, and carbenoxolone completely inhibited these reactions, while 7-oxo-DHEA only inhibited the NAD + -dependent reaction. Conversely, CS oxidation was not inhibited by 7α-OH-DHEA or 7-oxo-DHEA. PKMc and PKN did not convert 7-oxo-DHEA to 7-OH-DHEA with either NADPH or NADH. Finally, PKN contained a high affinity, NADPH-dependent 11βHSD that reduces DHC to CS. The GC effects on interconversion of DHEA metabolites may have clinical significance, since DHEA and its 7-oxidized derivatives have been proposed for treatment of human autoimmune and inflammatory disorders.

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“…Testosterone has no effect on 11␤-HSD1, at least in liver and kidney (239,418). However, estradiol, at high (pharmacological) levels, strongly represses 11␤-HSD1 in rodent liver and kidney (though not in hippocampus) (239,318,394,418), probably indirectly (316).…”

Section: F 11␤-hsd1 Regulationmentioning

confidence: 98%

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

Chapman

Holmes

Seckl

2013

Physiological Reviews

698

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

Cited by 51 publications

References 48 publications

Renal interstitial corticosterone and 11-dehydrocorticosterone in conscious rats

Renal interstitial corticosterone and 11-dehydrocorticosterone in conscious rats

Interactions between dehydroepiandrosterone and glucocorticoid metabolism in pig kidney: Nuclear and microsomal 11β-hydroxysteroid dehydrogenases

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

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