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Frank H. De Jong – One of the best experts on this subject based on the ideXlab platform.

  • expression and gene variation studies deny association of human hsd3b1 gene with aldosterone production or blood pressure
    American Journal of Hypertension, 2015
    Co-Authors: Germaine C Verwoert, Johannes Hofland, Najaf Amin, Francesco U S Mattaceraso, Eric J.g. Sijbrands, Albert Hofman, Anton H Van Den Meiracker, Andre G Uitterlinden, Cornelia M. Van Duijn, Frank H. De Jong

    Abstract:

    BACKGROUND: Recent evidence suggests that the type I 3β-hydroxysteroid dehydrogenase, a steroidogenic enzyme encoded by the HSD3B1 gene, could be involved in aldosterone production and that genetic variation in HSD3B1 is associated with blood pressure. These findings challenge the long-standing hypothesis that all adrenocortical steroidogenesis is executed by the type II iso-enzyme, encoded by HSD3B2. METHODS: To verify these findings, the Adrenal presence of HSD3B1 and its effect on aldosterone synthesis and blood pressure were studied in expression and genetic association analyses, respectively. Expression of HSD3B1 and HSD3B2 was investigated in various adrenocortical tissues (n = 15) and in primary Adrenal Cell cultures (n = 5) after stimulation with adrenocorticotropin and angiotensin II. Six tagging single nucleotide polymorphisms within the HSD3B1 gene were studied for association with blood pressure and hypertension in a meta-analysis of 4 Dutch cohorts (n = 11,192). RESULTS: HSD3B1 expression was minimal or absent in adrenocortical tissues, including 6 aldosterone-producing adenomas. In contrast with the ubiquitously expressed HSD3B2 mRNA, HSD3B1 levels were not stimulated by adrenocorticotropin or angiotensin II. No variants in the HSD3B1 gene were associated with blood pressure or the occurrence of hypertension. CONCLUSIONS: We found no evidence to support confirmation that HSD3B1 is involved in aldosterone synthesis in the human Adrenal cortex or that genetic variation in HSD3B1 affects blood pressure or hypertension, favoring the hypothesis that all adrenocortical steroidogenesis is primarily dependent on the type II 3β-hydroxysteroid dehydrogenase.

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  • Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression
    American Journal of Physiology-endocrinology and Metabolism, 2013
    Co-Authors: Johannes Hofland, Jacobie Steenbergen, Leo J. Hofland, Peter M Van Koetsveld, Marco Eijken, Francien H Van Nederveen, Geert Kazemier, Wouter W. De Herder, Richard A Feelders, Frank H. De Jong

    Abstract:

    Functional zonation of the Adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the Adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human Adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical Cell lines as well as in primary Adrenal Cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma Cells. This was confirmed in HAC15 Cells and for PMA in primary Adrenal Cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical Cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary c…

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  • Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression.
    American journal of physiology. Endocrinology and metabolism, 2013
    Co-Authors: Johannes Hofland, Jacobie Steenbergen, Leo J. Hofland, Peter M Van Koetsveld, Marco Eijken, Francien H Van Nederveen, Geert Kazemier, Wouter W. De Herder, Richard A Feelders, Frank H. De Jong

    Abstract:

    Functional zonation of the Adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the Adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human Adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical Cell lines as well as in primary Adrenal Cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma Cells. This was confirmed in HAC15 Cells and for PMA in primary Adrenal Cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical Cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of activin signaling during PKC stimulation through silencing of the inhibin βA-subunit or blocking of the activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or forskolin increased expression of the inhibin α-subunit and betaglycan, both of which are antagonists of activin action. These data indicate that activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation.

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William E Rainey – One of the best experts on this subject based on the ideXlab platform.

  • The effects of ACTH on steroid metabolomic profiles in human Adrenal Cells
    Journal of Endocrinology, 2011
    Co-Authors: Yewei Xing, Celso E. Gomez-sanchez, Michael A. Edwards, Clarence N. Ahlem, Michael R. Kennedy, Anthony Cohen, William E Rainey

    Abstract:

    The Adrenal glands are the primary source of mineralocorticoids, glucocorticoids, and the so-called Adrenal androgens. Under physiological conditions, cortisol and Adrenal androgen synthesis are controlled primarily by ACTH. Although it is well established that ACTH can stimulate steroidogenesis in the human Adrenal gland, the effect of ACTH on overall production of different classes of steroid hormones has not been defined. In this study, we examined the effect of ACTH on the production of 23 steroid hormones in adult Adrenal primary cultures and 20 steroids in the Adrenal Cell line, H295R. Liquid chromatography/tandem mass spectrometry analysis revealed that, in primary Adrenal Cell cultures, cortisol and corticosterone were the two most abundant steroid hormones produced with or without ACTH treatment (48 h). Cortisol production responded the most to ACTH treatment, with a 64-fold increase. Interestingly, the production of two androgens, androstenedione and 11β-hydroxyandrostenedione (11OHA), that were also produced in large amounts under basal conditions significantly increased after ACTH incubation. In H295R Cells, 11-deoxycortisol and androstenedione were the major products under basal conditions. Treatment with forskolin increased the percentage of 11β-hydroxylated products, including cortisol and 11OHA. This study illustrates that Adrenal Cells respond to ACTH through the secretion of a variety of steroid hormones, thus supporting the role of Adrenal Cells as a source of both corticosteroids and androgens.

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  • calmodulin dependent kinase i regulates Adrenal Cell expression of aldosterone synthase
    Endocrinology, 2002
    Co-Authors: Jennifer C Condon, Vincenzo Pezzi, Brad M Drummond, Su Yin, William E Rainey

    Abstract:

    Aldosterone synthase (CYP11B2) is expressed in the Adrenal glomerulosa and controls the capacity of the Adrenal glomerulosa to produce aldosterone. Herein, human NCI-H295R (H295R) adrenocortical Cells were used to define the calcium-dependent mechanisms regulating CYP11B2 gene transcription using reporter constructs containing CYP11B2 gene 5′-flanking DNA. Treatment of H295R Cells with calcium/calmodulin-dependent protein kinase (CaMK) inhibitor (KN93) or calmodulin inhibitor (calmidazolium) blocked angiotensin II and potassium (K+) stimulation of CYP11B2 reporter gene expression. To determine which CaMK regulates CYP11B2, vectors containing the complete coding sequences for CaMKI, CaMKII, and CaMKIV were transfected with the CYP11B2 reporter construct. CaMKI augmented reporter expression when Cellular calcium was elevated by ionomycin, whereas CaMKIV had a small effect, and CaMKII had no effect. To further study the role of CaMKs, constitutively active forms of CaMKI (CaMKI-295), II (CaMKII-290), and IV …

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  • differential regulation of aldosterone synthase and 11beta hydroxylase transcription by steroidogenic factor 1
    Journal of Molecular Endocrinology, 2002
    Co-Authors: Mary H Bassett, Yin Zhang, Colin Clyne, Perrin C White, William E Rainey

    Abstract:

    11β-Hydroxylase (hCYP11B1) and aldosterone synthase (hCYP11B2) are closely related isozymes with distinct roles in cortisol and aldosterone production respectively. Aldosterone synthase catalyzes the final step in aldosterone biosynthesis and is expressed only in the zona glomerulosa of the normal Adrenal. 11 β-Hydroxylase catalyzes the final reaction in the production of cortisol and is expressed at higher levels in the zona fasciculata. The mechanisms causing differential expression of these genes are not well defined. Herein, we demonstrate contrasting roles for the orphan receptor steroidogenic factor-1 (SF-1) in the regulation of human (h) CYP11B1 and hCYP11B2, Human NCI-H295R (H295R) or mouse Y-1 Cells were transiently transfected with luciferase reporter constructs containing 5′-flanking regions of hCYP11B1, hCYP11B2, human 17a-hydroxylase (hCYP17), human cholesterol side-chain cleavage (hCYP11A1) or mouse (m) cyp11b2 (mcyp11b2). Co-transfection of vectors encoding SF-1 increased expression of hCYP11B1, hCYP11A1 and hCYP17 constructs, but inhibited hCYP11B2 reporter activity. Murine, bovine and human SF-1 were unable to increase transcription of hCYP11B2 in H295R Cells. Both hCYP11B2 and mcyp11b2 promoter constructs were inhibited similarly by human SF-1. In mouse Y-1 Cells, reporter expression of hCYP11B2 and mcyp11b2 was very low compared with hCYP11B1 constructs, suggesting that this Adrenal Cell model may not be appropriate for studies of CYP11B2. Electrophoretic mobility shift assay demonstrated that SF-1 interacted with an element from both hCYP11B1 and hCYP11B2. However, mutation of this element, termed Ad4, did not prevent agonist stimulation of hCYP11B2 by angiotensin II or forskolin but blocked activity of hCYP11B1. In some, but not all, reports of genetic linkage analysis, a naturally occurring single nucleotide polymorphism within the Ad4 element of hCYP11B2 (-344C/T) has been associated with cardiovascular disease. Herein, we have demonstrated that this polymorphism influenced binding of SF-1 in electrophoretic mobility shift assays, with the C allele binding SF-1 more strongly than the T allele. However, when hCYP11B2 constructs containing these alleles were transfected into H295R Cells, there was no difference in agonist-stimulated expression or the response of either reporter construct to co-expression with human SF-1. Taken together, these data suggest that SF-1 and the Ad4 element are not major regulators of Adrenal hCYP11B2 gene expression. Thus far, hCYP11B2 is the first steroid hydroxylase gene which is not positively regulated by SF-1.

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Johannes Hofland – One of the best experts on this subject based on the ideXlab platform.

  • expression and gene variation studies deny association of human hsd3b1 gene with aldosterone production or blood pressure
    American Journal of Hypertension, 2015
    Co-Authors: Germaine C Verwoert, Johannes Hofland, Najaf Amin, Francesco U S Mattaceraso, Eric J.g. Sijbrands, Albert Hofman, Anton H Van Den Meiracker, Andre G Uitterlinden, Cornelia M. Van Duijn, Frank H. De Jong

    Abstract:

    BACKGROUND: Recent evidence suggests that the type I 3β-hydroxysteroid dehydrogenase, a steroidogenic enzyme encoded by the HSD3B1 gene, could be involved in aldosterone production and that genetic variation in HSD3B1 is associated with blood pressure. These findings challenge the long-standing hypothesis that all adrenocortical steroidogenesis is executed by the type II iso-enzyme, encoded by HSD3B2. METHODS: To verify these findings, the Adrenal presence of HSD3B1 and its effect on aldosterone synthesis and blood pressure were studied in expression and genetic association analyses, respectively. Expression of HSD3B1 and HSD3B2 was investigated in various adrenocortical tissues (n = 15) and in primary Adrenal Cell cultures (n = 5) after stimulation with adrenocorticotropin and angiotensin II. Six tagging single nucleotide polymorphisms within the HSD3B1 gene were studied for association with blood pressure and hypertension in a meta-analysis of 4 Dutch cohorts (n = 11,192). RESULTS: HSD3B1 expression was minimal or absent in adrenocortical tissues, including 6 aldosterone-producing adenomas. In contrast with the ubiquitously expressed HSD3B2 mRNA, HSD3B1 levels were not stimulated by adrenocorticotropin or angiotensin II. No variants in the HSD3B1 gene were associated with blood pressure or the occurrence of hypertension. CONCLUSIONS: We found no evidence to support confirmation that HSD3B1 is involved in aldosterone synthesis in the human Adrenal cortex or that genetic variation in HSD3B1 affects blood pressure or hypertension, favoring the hypothesis that all adrenocortical steroidogenesis is primarily dependent on the type II 3β-hydroxysteroid dehydrogenase.

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  • Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression
    American Journal of Physiology-endocrinology and Metabolism, 2013
    Co-Authors: Johannes Hofland, Jacobie Steenbergen, Leo J. Hofland, Peter M Van Koetsveld, Marco Eijken, Francien H Van Nederveen, Geert Kazemier, Wouter W. De Herder, Richard A Feelders, Frank H. De Jong

    Abstract:

    Functional zonation of the Adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the Adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human Adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical Cell lines as well as in primary Adrenal Cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma Cells. This was confirmed in HAC15 Cells and for PMA in primary Adrenal Cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical Cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary c…

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  • Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression.
    American journal of physiology. Endocrinology and metabolism, 2013
    Co-Authors: Johannes Hofland, Jacobie Steenbergen, Leo J. Hofland, Peter M Van Koetsveld, Marco Eijken, Francien H Van Nederveen, Geert Kazemier, Wouter W. De Herder, Richard A Feelders, Frank H. De Jong

    Abstract:

    Functional zonation of the Adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the Adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human Adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical Cell lines as well as in primary Adrenal Cell cultures. Inhibin βA-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma Cells. This was confirmed in HAC15 Cells and for PMA in primary Adrenal Cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical Cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of activin signaling during PKC stimulation through silencing of the inhibin βA-subunit or blocking of the activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or forskolin increased expression of the inhibin α-subunit and betaglycan, both of which are antagonists of activin action. These data indicate that activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation.

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