A role for the NGFI-B family in adrenal zonation and adrenocortical disease
A role for the NGFI-B family in adrenal zonation and adrenocortical disease
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DOI：
10.1081/erc-200043715
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发表时间：
2004-01-01
影响因子：
2.1
通讯作者：
Rainey, WE
中科院分区：
文献类型：
--
作者：
Bassett, MH;White, PC;Rainey, WE
人类肾上腺皮质的三个区域在功能上有所不同，肾小球产生醛固酮，束状肌产生皮质醇，网状肌产生DHEA/DHEAS。这种功能分区很大程度上是由于类固醇生成酶的区域特异性表达。最近的证据表明，孤儿核受体 NGFI-B 家族（特别是 NURR1 和 NGFI-B）在两种关键类固醇生成酶（醛固酮合酶 (CYP11B2) 和 3 β-羟基类固醇脱氢酶 (HSD3B2)）的区域特异性表达中发挥作用。在此，我们讨论了一些证据，这些证据表明 NURR1 (NR4A2) 在肾小球 CYP11B2 表达以及 CYP11B2 基因表达失调中发挥作用，如在产生醛固酮的腺瘤 (APA) 中所见，APA 是内分泌高血压的主要原因。 NURR1 似乎对 CYP11B2 转录很重要，并且在肾小球和 APA 中含量较高。血管紧张素 II 治疗也容易增加其在肾上腺细胞中的表达。 HSD3B2 是一种类固醇代谢酶，对于肾上腺产生盐皮质激素和糖皮质激素至关重要。因此，HSD3B2 在产生这些类固醇的肾小球和束状肌中以高水平表达，但在主要产生 DHEA 的肾上腺网状肌中以低水平表达。我们最近证明NGFI-B（nur77或NR4A1）在HSD3B2转录的调节中发挥重要作用，并且可能在肾上腺的功能分区中发挥重要作用。免疫组织化学证实，在成人和胎儿肾上腺内，NGFI-B 的表达与 HSD3B2 的表达平行。瞬时转染表明 NGFI-B 家族成员增强了 HSD3B2 报告基因活性，但对 17α-羟化酶 (CYP17) 启动子构建体没有影响。综上所述，这些结果表明转录因子 NGFI-B 家族通过调节 CYP11B2 和 HSD3B2 基因转录在建立人肾上腺功能分区中发挥作用。
The three zones of the human adrenal cortex are functionally distinct with the glomerulosa producing aldosterone, the fasciculata producing cortisol, and the reticularis producing DHEA/DHEAS. This functional zonation is largely due to the zone-specific expression of steroidogenic enzymes. Recent evidence suggests a role for the NGFI-B family of orphan nuclear receptors (particularly NURR1 and NGFI-B) in the zone-specific expression of two key steroidogenic enzymes, aldosterone synthase (CYP11B2) and 3 beta-hydroxysteroid dehydrogenase (HSD3B2). Herein we discuss the evidence that suggests a role for NURR1 (NR4A2) in the expression of CYP11B2 in the glomerulosa as well as in the dysregulation of CYP11B2 gene expression as is seen in aldosterone-producing adenoma (APA), a major cause of endocrine hypertension. NURR1 appears to be important for CYP11B2 transcription and is found at higher levels in glomerulosa and in APA. Its expression in adrenal cells is also readily increased by angiotensin II treatment. HSD3B2 is a steroid-metabolizing enzyme that is essential for adrenal production of mineralocorticoids and glucocorticoids. Thus, HSD3B2 is expressed at high levels in the glomerulosa and fasciculata where these steroids are produced but at low levels in the adrenal reticularis, which produces mainly DHEA. We recently demonstrated that NGFI-B (nur77 or NR4A1) plays an important role in the regulation of HSD3B2 transcription and may play an important role in the functional zonation of the adrenal gland. Immunohistochemistry confirmed that, within adult and fetal adrenal gland, NGFI-B expression paralleled expression of HSD3B2. Transient transfections demonstrated that NGFI-B family members enhanced HSD3B2 reporter activity but had no effect on a 17alpha-hydroxylase (CYP17) promoter construct. Taken together these results suggest that the NGFI-B family of transcription factors plays a role in establishing the functional zonation of the human adrenal by regulating CYP11B2 and HSD3B2 gene transcription.