The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production
The orphan nuclear receptors NURR1 and NGFIB regulate adrenal aldosterone production
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DOI：
10.1210/me.2003-0005
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发表时间：
2004-02-01
影响因子：
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通讯作者：
Rainey, WE
中科院分区：
文献类型：
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作者：
Bassett, MH;Suzuki, T;Rainey, WE
肾上腺皮质肾小球中的醛固酮生物合成受CYP 11B 2（编码醛固酮合成酶）的转录调节。在人H295 R肾上腺皮质细胞中，比较了神经生长因子诱导克隆B（NGFI B）（NR 4A 1）、Nur相关因子1（NR 4A 2）和类固醇生成因子-1（SF-1）（NR 5A 1）对人CYP 11 B2（hCYP 11 B2）和hCYP 11 B1（11 β-羟化酶）转录的影响。NGFIB和CYP 11 R1可增加hCYP 11B 2的表达。尽管SF-1可激活hCYP 11 B1，但与SF-1共转染可抑制NGFIB和NGF 1 R1对hCYP 11 B2的激活。血管紧张素II（Ang）II是体内hCYP 11 B2表达的主要调节因子，可强烈诱导NGFIB和NGF 1 R1的转录和蛋白水平。hCYP 11 B2启动子的顺序缺失和突变鉴定了两个功能性NGFIB应答元件（NBRE），一个位于-766/-759（NBRE-1），而先前研究的Ad 5元件位于-129/-114。EMSA表明，这两种元件都结合NGFIB和NGFR 1。在人类肾上腺中，NGF 1 R 1免疫反应性优先定位于肾小球，并在较小程度上在束状体，而NGFIB检测到在这两个区域。钙调蛋白激酶抑制剂KN 93部分阻断K+刺激的NGFIB和NGFR 1的转录。KN 93可部分抑制Ang Ⅱ对NGFIB 1 mRNA表达的影响，但对NGFIB表达无影响。NBRE-1、Ad 5和Ad 1/cAMP反应元件（CRE）顺式元件的突变降低了hCYP 11 B2的基础水平和Ang II诱导的水平，表明所有三个元件对最大转录活性都很重要。我们的研究结果表明，NGFIB和CRISPR 1是hCYP 11 B2表达的关键调节因子，并可能部分介导Ang II对hCYP 11 B2的调节。
Aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex is regulated by transcription of CYP11B2 ( encoding aldosterone synthase). The effects of nerve growth factor-induced clone B ( NGFIB) (NR4A1), Nur-related factor 1 (NURR1) (NR4A2), and steroidogenic factor-1 (SF-1) (NR5A1) on transcription of human CYP11B2 (hCYP11B2) and hCYP11B1 (11beta-hydroxylase) were compared in human H295R adrenocortical cells. hCYP11B2 expression was increased by NGFIB and NURR1. Although hCYP11B1 was activated by SF-1, cotransfection with SF-1 inhibited activation of hCYP11B2 by NGFIB and NURR1. NGFIB and NURR1 transcript and protein levels were strongly induced by angiotensin (Ang) II, the major regulator of hCYP11B2 expression in vivo. Sequential deletion and mutagenesis of the hCYP11B2 promoter identified two functional NGFIB response elements (NBREs), one located at - 766/ - 759 (NBRE-1) and the previously studied Ad5 element at - 129/ - 114. EMSAs suggested that both elements bound NGFIB and NURR1. 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. The calmodulin kinase inhibitor KN93 partially blocked K+-stimulated transcription of NGFIB and NURR1. KN93 partially inhibited the effect of Ang II on NURR1 mRNA levels but did not modify the effect on expression of NGFIB. Mutation of the NBRE-1, Ad5, and Ad1/cAMP response element (CRE) cis-elements reduced both basal and Ang II-induced levels of hCYP11B2, demonstrating that all three elements are important for maximal transcriptional activity. Our results suggest that NGFIB and NURR1 are key regulators of hCYP11B2 expression and may partially mediate the regulation of hCYP11B2 by Ang II.