Prolonged fasting activates Nrf2 in postweaned elephant seals

Abstract

Summary Elephant seals naturally experience prolonged periods of absolute food and water deprivation (fasting). In humans, rats and mice, prolonged food deprivation activates the renin angiotensin system (RAS) and increases oxidative damage. In elephant seals, prolonged fasting activates RAS without increasing oxidative damage likely due to an increase in antioxidant defenses. The mechanism leading to the up-regulation of antioxidant defenses during prolonged fasting remains elusive. Therefore, we investigated if prolonged fasting activates the redox-sensitive transcription factor Nrf2, which controls the expression of antioxidant genes, and if such activation is potentially mediated by systemic increases in RAS. Blood and skeletal muscle samples were collected from seals fasting for 1, 3, 5 and 7 weeks. Nrf2 activity and nuclear content increased by 76% and 2.5 fold at week 7. Plasma angiotensin II (Ang II) and transforming growth factor β (TGF-β) were 50-fold and 3-fold higher at week 7 than at week 1. Smad2 phosphorylation, an effector of Ang II and TGF signaling, increased by 120% at week 7 and by 84% in response to intravenously infused Ang II. NADPH oxidase 4 (Nox4) mRNA expression, which is controlled by smad proteins, increased 5-fold at week 7, while Nox4 protein expression, which can activate Nrf2, was 2.5-fold higher at wk 7 than at wk 1. Results demonstrate that prolonged fasting activates Nrf2 in elephant seals and that RAS stimulation can potentially result in increased Nox4 through Smad phosphorylation. Results also suggest that Nox4 is essential to sustain the hormetic adaptive response to oxidative stress in fasting seals.