RT Journal Article
SR Electronic
T1 Prolonged fasting activates Nrf2 in post-weaned elephant seals
JF The Journal of Experimental Biology
JO J. Exp. Biol.
FD The Company of Biologists Ltd
SP 2870
OP 2878
DO 10.1242/jeb.081927
VO 216
IS 15
A1 Vázquez-Medina, José Pablo
A1 Soñanez-Organis, José G.
A1 Rodriguez, Ruben
A1 Viscarra, Jose A.
A1 Nishiyama, Akira
A1 Crocker, Daniel E.
A1 Ortiz, Rudy M.
YR 2013
UL http://jeb.biologists.org/content/216/15/2870.abstract
AB 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. Ang IIangiotensin IIARBangiotensin receptor type 1 blockerAT1angiotensin receptor type 1EpREelectrophilic responsive elementGSHglutathioneH2O2hydrogen peroxideHPAhypothalamic–pituitary–adrenal axisKeap1kelch-like ECH-associated protein 1NoxNADPH oxidaseNrf2erythroid 2-related factor 2RASrenin–angiotensin systemTGF-βtransforming growth factor βXOxanthine oxidase