Division of Endocrinology and Hypertension, Department of Internal Medicine, Japan.
J Hypertens. 2011 Jun;29(6):1185-95. doi: 10.1097/HJH.0b013e32834626bb.
Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (NURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues.
We collected tissues of artery (n = 9), cardiomyopathy muscle (n = 9), heart muscle (noncardiomyopathy) (n = 6), adrenal gland (n = 9) and aldosterone-producing adenoma (APA) (n = 9). 5'-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs).
In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5'-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues.
NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland.
核受体参与多种功能，包括醛固酮的生成。核受体家族 NR4A [神经生长因子诱导克隆 B（NGFIB）、Nur 相关因子 1（NURR1）和神经元衍生孤儿受体 1（NOR1）]和 NR2F [鸡卵清蛋白上游启动子转录因子 1（COUP-TFI）、COUP-TFII 和 NR2F6）激活，而 NR5A1 [类固醇生成因子 1（SF1）]抑制 CYP11B2（醛固酮合酶）基因转录。本研究旨在阐明心血管组织和肾上腺组织中核受体差异调节的机制。
我们收集了动脉（n=9）、心肌病肌肉（n=9）、心脏肌肉（非心肌病）（n=6）、肾上腺（n=9）和醛固酮产生腺瘤（APA）（n=9）的组织。5'-快速扩增 cDNA 末端（RACE）鉴定转录起始位点。多重逆转录 PCR（RT-PCR）确定了非编码外显子 1（ANEs）的替代使用。
在肾上腺皮质 H295R 细胞中，血管紧张素 II、KCl 或 cAMP 均刺激 CYP11B2 转录并上调 NR4A，而下调 NR2F 和 NR5A1。5'-RACE 和 RT-PCR 显示在心血管和肾上腺组织中存在 NGFIB（NR4A1）的四个 ANEs、NURR1（NR4A2）的三个、NOR1（NR4A3）的两个和 SF1（NR5A1）的两个。定量多重 RT-PCR 显示 NR4A 和 NR5A1 以组织特异性方式差异地使用多个 ANEs。APA 和动脉之间 ANEs 的使用存在显著差异。在心肌病和非心肌病之间观察到 NGFIB 和 NOR1 的 ANEs 使用的变化。与心脏和肾上腺组织相比，动脉中的 NR4A mRNA 水平较高，而与心血管组织相比，肾上腺组织中的 NR5A1 mRNA 水平极高。
NR4A 和 NR5A1 基因在启动子使用方面非常复杂。ANEs 的使用可能与心脏和肾上腺的病理生理学有关。
