Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis

Yudai Torihata, Kiyotaka Asanuma, Katsunori Iijima, Tetsuhiko Mikami, Shin Hamada, Naoki Asano, Tomoyuki Koike, Akira Imatani, Atsushi Masamune, Tooru Shimosegawa

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


Background: Gastroesophageal reflux disease is more common in males than in females. The enhanced antioxidative capacity of estrogen in females might account for the gender difference. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in the host defense mechanism against oxidative stress. Aims: This study aimed to clarify the role of Nrf2 in reflux-induced esophageal inflammation, focusing on the gender difference and nitric oxide. Methods: Gastroesophageal reflux was surgically induced in male and female rats. Nitrite and ascorbic acid were administered for 1 week to provoke nitric oxide in the esophageal lumen. Male rats with gastroesophageal reflux were supplemented with 17β-estradiol or tert-butylhydroquinone, an Nrf2-inducing reagent. Esophageal squamous cell carcinoma KYSE30 cells were treated with 17β-estradiol. Nrf2 expression was examined by Western blotting and quantitative real-time PCR. Antioxidant gene expression profiles were examined by a PCR array. Results: In the presence of nitric oxide, reflux-induced esophageal damage was less evident, whereas esophageal expression of Nrf2 and its target genes such as Nqo1 was more evident in female or male rats supplemented with 17β-estradiol than in male rats. 17β-Estradiol increased nuclear Nrf2 expression in KYSE30 cells. tert-Butylhydroquinone increased tissue Nqo1 mRNA expression, leading to a reduction in reflux-induced esophageal damage. Conclusions: Estrogen-dependent Nrf2 expression might contribute to protection against the development of gastroesophageal reflux disease in females.

Original languageEnglish
Pages (from-to)345-355
Number of pages11
JournalDigestive Diseases and Sciences
Issue number2
Publication statusPublished - 2018 Feb 1


  • Antioxidant
  • Barrett’s esophagus
  • Gastroesophageal reflux disease
  • Gender
  • Nitric oxide
  • Nuclear factor erythroid 2-related factor 2
  • Oxidative stress


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