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Titolo:
Phenotypic analysis of mice bearing targeted deletions of 11 beta-hydroxysteroid dehydrogenases 1 and 2 genes
Autore:
Holmes, MC; Kotelevtsev, Y; Mullins, JJ; Seckl, JR;
Indirizzi:
Western Gen Hosp, Mol Med Ctr, Dept Clin Neurosci, Edinburgh EH4 2XU, Midlothian, Scotland Western Gen Hosp Edinburgh Midlothian Scotland EH4 2XU dlothian, Scotland Univ Edinburgh, Dept Med Sci, Edinburgh, Midlothian, Scotland Univ Edinburgh Edinburgh Midlothian Scotland burgh, Midlothian, Scotland Univ Edinburgh, Dept Cardiol, Edinburgh, Midlothian, Scotland Univ Edinburgh Edinburgh Midlothian Scotland burgh, Midlothian, Scotland
Titolo Testata:
MOLECULAR AND CELLULAR ENDOCRINOLOGY
fascicolo: 1-2, volume: 171, anno: 2001,
pagine: 15 - 20
SICI:
0303-7207(20010122)171:1-2<15:PAOMBT>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
APPARENT MINERALOCORTICOID EXCESS; RECEPTOR; TYPE-2; CLONING; PURIFICATION; HYPERTENSION; COMPLEX; ENZYME;
Keywords:
blood pressure; corticosterone; glucocorticoids; gluconeogenesis; 11 beta-hydroxysteroid dehydrogenase; hypothalamo-pituitary adrenal axis; minarlocorticoid; SAME; transgenic;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
17
Recensione:
Indirizzi per estratti:
Indirizzo: Holmes, MC Western Gen Hosp, Mol Med Ctr, Dept Clin Neurosci, Edinburgh EH4 2XU, Midlothian, Scotland Western Gen Hosp Edinburgh Midlothian ScotlandEH4 2XU cotland
Citazione:
M.C. Holmes et al., "Phenotypic analysis of mice bearing targeted deletions of 11 beta-hydroxysteroid dehydrogenases 1 and 2 genes", MOL C ENDOC, 171(1-2), 2001, pp. 15-20

Abstract

The glucocorticoid metabolising enzymes, 11 beta -hydroxysteroid dehydrogenases (11 beta -HSD), play a critical role in determining the availability of glucocorticoids to activate their receptors and hence modulate target gene transcription. There are two isozymes. 11 beta -HSD-1 and -2, which act in opposing directions. 11 beta -HSD-2 acts as a dehydrogenase. converting active corticosterone (cortisol in humans) to its inactive 11-keto derivative (11-dehydrocorticosterone in rodents and cortisone in humans), whereas 11 beta -HSD-1 acts as a reductase. regenerating active glucocorticoids in atissue-specific manner, owing to the lack of specific inhibitors of these enzymes, it has been difficult to confirm the roles and determine the importance of these enzymes in vivo. Hence. to address this, we produced transgenic mice with null-mutations in the genes encoding the 11 beta -HSD-1 or 11beta -HSD-2 enzymes. 11 beta -HSD-2 -/- mice show signs of hypertension, hypotonic polyuria, hypokalemia and hypochloremia. These symptoms arise fromillicit activation of mineralocorticoid receptors by glucocorticoids. in the;absence of the protective action of 11 beta -HSD-2. The phenotype is directly comparable to the Syndrome of Apparent Mineralocorticoid Excess, seenin humans, with mutations in the 11 beta -HSD-2 gene. Mice lacking 11 beta-HSD-1, however, show a more subtle phenotype with reduced activation of glucocorticoid-induced processes. They were unable to convert 11-dehydrocorticosterone to corticosterone in vivo, confirming 11 beta -HSD-1 as the sole11-reductase in the mouse. They have elevated circulating levels of plasmacorticosterone levels and adrenal hyperplasia, but they also have attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to fasting and lower glucose levels in response to obesity or stress. Overall. these transgenic models have proved very useful for elucidating the roles of 11 beta -HSDs in vivo and will be a unique resource for investigating the importance of each enzyme in the diverse actions of glucocorticoids. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 13/12/18 alle ore 23:56:53