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Mary H. White, William E. Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is regulated by transcription of CYP11B2 encoding aldosterone synthase. In human adrenals, NURR1 immunoreactivity was preferentially localized in the zona glomerulosa and to a lesser degree in the zona fasciculata, whereas NGFIB was detected in both zones. In humans, the synthesis of aldosterone, the major mineralocorticoid, relies on CYP11B2 aldosterone synthase , a steroid-metabolizing cytochrome P CYP.
This enzyme converts deoxycorticosterone to aldosterone 1 , 2. It is expressed only within the adrenal zona glomerulosa and is under the control of circulating levels of angiotensin Ang II and potassium 3 — 5. Deoxycorticosterone is also synthesized in the fasciculata at levels that would lead to mineralocorticoid excess if it were converted to aldosterone. Thus, the ability of the adrenal cortex to control aldosterone production is the result of limiting the expression of human CYP11B2 hCYP11B2 to the zona glomerulosa.
The trans -acting factors that regulate hCYP11B2 expression remain poorly defined. The orphan nuclear receptor, steroidogenic factor-1 SF-1 , is a major regulator of other steroid hydroxylase genes including hCYP11B1 7 , 8 , but it fails to stimulate and indeed represses expression of hCYP11B2 9. Other transcription factors that are expressed in the adrenal cortex include the NGFIB family of orphan nuclear receptors termed the NR4A subgroup for nuclear receptor subgroup 4 Both are expressed in the zona glomerulosa, the site of hCYP11B2 expression.
As expected from our prior study 9 , SF-1 failed to activate the hCYP11B2 promoter at any of the concentrations tested. Total RNA was also isolated from adult adrenal gland. Deoxyribonuclease I footprint analysis of the bovine CYP11B promoter had previously identified six cis -elements, termed Ad1 through Ad6 Adrenal 1—6 , which bound nuclear proteins 16 — 18 ; similar sequences have been identified in the hCYP11B2 gene As shown in Fig.
