Estrogen-Dependent Nrf2 Expression Protects Against Reflux-Induced Esophagitis

Area of Science:

• Gastroenterology
• Molecular Biology
• Endocrinology

Background:

• Gastroesophageal reflux disease (GERD) shows a higher prevalence in males compared to females.
• Estrogen's potent antioxidant properties are hypothesized to contribute to this observed gender disparity.
• Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator in the cellular defense against oxidative stress.

Purpose of the Study:

• To investigate the role of Nrf2 in reflux-induced esophageal inflammation.
• To elucidate the gender-specific differences in GERD pathogenesis.
• To examine the involvement of nitric oxide in the Nrf2 pathway during reflux esophagitis.

Main Methods:

• Surgically induced gastroesophageal reflux in male and female rats.
• Administration of nitrite and ascorbic acid to generate nitric oxide in the esophageal lumen.
• Supplementation of male rats with 17β-estradiol or tert-butylhydroquinone (an Nrf2 activator) and analysis of Nrf2 expression and antioxidant gene profiles.

Main Results:

• Reflux-induced esophageal damage was reduced in the presence of nitric oxide.
• Female rats and male rats supplemented with 17β-estradiol exhibited increased esophageal Nrf2 and Nqo1 expression compared to control males.
• 17β-estradiol enhanced nuclear Nrf2 translocation in esophageal cancer cells, while tert-butylhydroquinone upregulated Nqo1 mRNA, mitigating reflux damage.

Conclusions:

• Estrogen-mediated activation of Nrf2 signaling appears to confer protection against GERD development in females.
• Nrf2 plays a critical role in mitigating oxidative stress and inflammation in the esophagus.
• Targeting the Nrf2 pathway could offer therapeutic potential for GERD treatment.