title: Prolonged fasting activates Nrf2 in post-weaned elephant seals.
abstract: 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 upregulation of antioxidant defenses during prolonged fasting remains elusive. Therefore, we investigated whether 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 167% at week 7. Plasma angiotensin II (Ang II) and transforming growth factor β (TGF-β) were 5000% and 250% higher at week 7 than at week 1. Phosphorylation of Smad2, 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 430% at week 7, while Nox4 protein expression, which can activate Nrf2, was 170% higher at week 7 than at week 1. These results demonstrate that prolonged fasting activates Nrf2 in elephant seals and that RAS stimulation can potentially result in increased Nox4 through Smad phosphorylation. The results also suggest that Nox4 is essential to sustain the hormetic adaptive response to oxidative stress in fasting seals.
authors.affiliation: School of Natural Sciences, University of California Merced, Merced, CA, USA. jvazquez-medina@ucmerced.edu
authors.forename: José Pablo
authors.initials: JP
authors.lastname: Vázquez-Medina
authors.forename: José G
authors.initials: JG
authors.lastname: Soñanez-Organis
authors.forename: Ruben
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Jose A
authors.initials: JA
authors.lastname: Viscarra
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Crocker
authors.forename: Rudy M
authors.initials: RM
authors.lastname: Ortiz
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D017124:Conserved Sequence; D005215:Fasting / Q000097:blood / Q000502:physiology*; D005260:Female; D008297:Male; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D019255:NADPH Oxidases / Q000737:chemistry / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051381:Rats; D046048:Seals, Earless / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood; D014886:Weaning
chemical_list: D051267:NF-E2-Related Factor 2; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019255:NADPH Oxidases
keywords: Nox4; antioxidants; hormesis; oxidative stress; renin–angiotensin system; starvation