The sheep kidney contains a novel unidirectional, high affinity NADP+-dependent 11β-hydroxysteroid dehydrogenase (11β-HSD-3)

Gómez-Sánchez, Elise P.; Ganjam, Venkataseshu K.; Chen, Yuan Jian; Cox, Diana L.; Zhou, Mingyi; Thanigaraj, Srihari; Gómez-Sánchez, Celso E.

doi:10.1016/s0039-128x(97)00011-1

Cited by 38 publications

(20 citation statements)

References 30 publications

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“…This further suggests that in the pig kidney, the enzymatic systems oxidizing CS most likely are different than those catalyzing the oxidation of 7α-OH-DHEA. The similarity in rates of CS oxidation manifested by both fractions and the pyridine nucleotide specificity found herein for the pig kidney is different than the pattern observed with sheep kidney [10]. In sheep kidney, the nuclear fraction oxidized more cortisol in presence of NAD + than with NADP + , while the microsomal fraction showed preference for NADP + -dependent rather than NAD + -dependent conversion.…”

Section: Discussioncontrasting

confidence: 85%

“…Our finding that CS is oxidized to DHC in presence of either nucleotide does not fit the conclusion in the literature that NAD + -dependent microsomal 11βHSD2 as the sole kidney 11βHSD that oxidizes 11-hydroxy-GC in kidney [30]. Our results are in agreement with the NAD + -and NADP + -dependent oxidation reactions of CS found in sheep kidney [10]. The LLC-PK1 cell line derived from the kidney of a normal healthy male pig oxidizes cortisol in the presence of NAD + , as well as of NADP + , and has been proposed to contain two different forms of 11βHSD [31].…”

Section: Discussioncontrasting

confidence: 54%

“…In human kidney nuclei, immuno-reactive human 11βHSD2 accounted for 40% of total cellular 11βHSD2 protein content [7,8]. In kidney from rat and sheep, a third dehydrogenase (11βHSD3) was shown to be present in membranes of Golgi apparatus and mitochondria, while 11βHSD2 is preferentially located in the nuclear membrane [9,10]. Because of their differing sub-cellular distribution and function in GC metabolism, 11βHSDs are considered gatekeepers that prevent excess GC in plasma from binding to nuclear MR.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussioncontrasting

confidence: 85%

Section: Discussioncontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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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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“…These data support the suggestion that another NADP ϩ -dependent enzyme with 11␤HSD activity exists. There have been other reports of 11␤HSD activity that does not appear to be due to either 11␤HSD1 or -2, but as yet no other enzyme has been isolated or gene cloned (10,12,18). Despite a large increase in message and protein measured by both Western blot and immunocytochemistry for the 11␤HSD2 enzyme, in vivo activity, as measured by the ratio of urinary corticosterone to 11-dehydrocorticosterone, did not change in estradiol-treated rats.…”

Section: Discussionmentioning

confidence: 79%

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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“…If this is the case, the expression of 11HSD1 may create a favourable environment for increasing oestrogen production by decreasing levels of cortisol which has been shown to inhibit oestrogen production and LH-receptor expression in cultured bovine granulosa cells (Kawate et al 1993). Otherwise, this phenomenon might be attributable to the activity of a third 11 -HSD isozyme (11 -HSD type3), a dehydrogenase, the presence of which was implicated in the sheep kidney (Gomez-Sanchez et al 1997). Nevertheless, a further study is necessary to characterize bovine 11HSD1.…”

Section: Discussionmentioning

confidence: 99%

Expression of 11beta-hydroxysteroid dehydrogenases in bovine follicle and corpus luteum

Tetsuka¹,

Yamamoto²,

Hayashida³

et al. 2003

Journal of Endocrinology

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In glucocorticoid target organs, local concentrations of active glucocorticoid are determined by the relative expression of two 11 -hydroxysteroid dehydrogenases (HSDs): bi-directional 11 -HSD type1 (11HSD1) that mainly activates cortisone to cortisol, and dehydrogenase 11 -HSD type2 (11HSD2) that inactivates cortisol to cortisone. In this study, we examined the expression of mRNA encoding these two 11 -HSDs in bovine granulosa cells harvested from preovulatory follicles and corpora lutea (CL). Ovaries were obtained from Holstein cows at a local slaughterhouse. Follicles larger than 10 mm in diameter and CL were dissected and follicular fluid and granulosa cells were taken. Corpora lutea were weighed and their stages were morphologically assessed (stage I, days 1-4; stage II, days 5-10; stage III, days 11-17; stage IV, days 8-20). Follicles were classified into four groups according to their hormonal status (oestradiol (E 2 ): progesterone (P 4 )>1: oestrogen active; E 2 :P 4 <1: oestrogen inactive) and stage of the oestrous cycle (luteal or follicular phase). Total RNA was extracted with phenol-chloroform and subjected to a semi-quantitative RT-PCR for 11HSD1, 11HSD2 and -actin. Concentrations of steroids in follicular fluid were determined by an enzyme immunoassay. In granulosa cells, only 11HSD1 mRNA was detected. There was a negative correlation between the expression of 11HSD1 and the concentration of cortisol in follicular fluid (P<0·05), indicating 11HSD1 may act as a dehydrogenase in the bovine follicle. Both types of 11 -HSDs were expressed in CL. The levels of mRNA for both isozymes were high in stage I and II, and were decreased in stage III CL. In stage IV CL, the expression of 11HSD2 but not 11HSD1 mRNA increased. These results indicate that the bovine granulosa cells and CL express 11HSD1 and 11HSD2, and they may play an important physiological role in the bovine ovary through modulating the local glucocorticoid environment.

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The sheep kidney contains a novel unidirectional, high affinity NADP+-dependent 11β-hydroxysteroid dehydrogenase (11β-HSD-3)

Cited by 38 publications

References 30 publications

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

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

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

Expression of 11beta-hydroxysteroid dehydrogenases in bovine follicle and corpus luteum

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