Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues

Masashi Demura, Fen Wang, Takashi Yoneda, Shigehiro Karashima, Shunsuke Mori, Masashi Oe, Mitsuhiro Kometani, Toshitaka Sawamura, Yuan Cheng, Yuji Maeda, Mikio Namiki, Hidekazu Ino, Noboru Fujino, Katsuharu Uchiyama, Toshinari Tsubokawa, Masakazu Yamagishi, Yasuhiro Nakamura, Katsuhiko Ono, Hironobu Sasano, Yoshiki DemuraYoshiyu Takeda

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Objective: 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. Methods: 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). Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)1185-1195
Number of pages11
JournalJournal of hypertension
Volume29
Issue number6
DOIs
Publication statusPublished - 2011 Jun

Keywords

  • CYP11B2
  • adrenal cortex
  • aldosterone-producing adenoma
  • artery
  • cardiac muscle
  • noncoding exon
  • nuclear receptor

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Demura, M., Wang, F., Yoneda, T., Karashima, S., Mori, S., Oe, M., Kometani, M., Sawamura, T., Cheng, Y., Maeda, Y., Namiki, M., Ino, H., Fujino, N., Uchiyama, K., Tsubokawa, T., Yamagishi, M., Nakamura, Y., Ono, K., Sasano, H., ... Takeda, Y. (2011). Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues. Journal of hypertension, 29(6), 1185-1195. https://doi.org/10.1097/HJH.0b013e32834626bb