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Issue 2, 2014
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Nrf2 activation in the liver of rats subjected to a preconditioning sub-chronic iron protocol

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Abstract

Sub-chronic iron (Fe) administration induces liver oxidative stress upregulating cytoprotective mechanisms that may involve redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2). We aimed to investigate whether Fe activates Nrf2, in relation to its negative regulator Kelch-like ECH associated protein 1 (Keap1), with consequent antioxidant enzyme induction. Sprague-Dawley rats received six Fe doses (50 mg kg−1) on alternate days or saline (controls), a protocol that abrogates ischemia-reperfusion liver injury. Liver reduced glutathione (GSH) content and Nrf2 (Western blot) were measured 24 h after each Fe dose. Increased hepatic Fe deposition (Perls staining) was paralleled by reversible GSH depletion and enhancements in nuclear Nrf2 content and in nuclear/cytosolic Nrf2 ratios. A similar profile was observed for heme oxygenase-1 (HO-1) and NADPH–quinone oxidoreductase 1 (NQO-1) contents, antioxidant enzymes that significantly correlated with nuclear/cytosolic Nrf2 ratios. Normalization of Fe-induced oxidative stress status occurred concomitantly with that of Nrf2 and with the Nrf2-dependent HO-1 and NQO-1 expression, which are associated with delayed enhancement in cytosolic Keap1 levels. This is in agreement with the significant inverse correlation of nuclear/cytosolic Nrf2 ratios with those of nuclear Keap1/Nrf2, suggesting a negative feed-back mechanism normalizing Nrf2 signaling. In conclusion, sub-chronic Fe administration leads to transient liver oxidative stress development and Nrf2 activation, as evidenced by early GSH depletion, enhanced nuclear Nrf2 protein levels, and HO-1 and NQO-1 induction, with late normalization of these changes being related to Keap1 upregulation.

Graphical abstract: Nrf2 activation in the liver of rats subjected to a preconditioning sub-chronic iron protocol

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Article information


Submitted
11 Jul 2013
Accepted
20 Nov 2013
First published
22 Nov 2013

Food Funct., 2014,5, 243-250
Article type
Paper

Nrf2 activation in the liver of rats subjected to a preconditioning sub-chronic iron protocol

P. Morales, R. Vargas, L. A. Videla and V. Fernández, Food Funct., 2014, 5, 243
DOI: 10.1039/C3FO60265F

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