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Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia-reperfusion injury

Martin O. Leonard^*,1, Niamh E. Kieran^*, Katherine Howell^*, Melissa J. Burne, Raghu Varadarajan, Saravanakumar Dhakshinamoorthy, Alan G. Porter, Cliona O’Farrelly, Hamid Rabb and Cormac T. Taylor^*

^* School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research and

Education and Research Center, St. Vincent’s University Hospital, University College Dublin, Ireland;

Nephrology Division, Johns Hopkins University Hospital, Baltimore, Maryland, USA; and

Institute of Molecular and Cell Biology, Singapore, Republic of Singapore

¹Correspondence: School of Medicine and Medical Sciences, The Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. E-mail: martin.leonard{at}ucd.ie

ABSTRACT

Tissue reoxygenation following hypoxia is associated with ischemia-reperfusion injury (IRI) and may signal the development of ischemic preconditioning, an adaptive state that is protective against subsequent IRI. Here we used microarray RNA analysis of in vivo and in vitro models of IRI to delineate the underlying molecular mechanisms. Microarray analysis of renal tissue after ischemia-reperfusion revealed a number of highly up-regulated antioxidant genes including aldehyde dehydrogenases (ALDH1A1 and ALDH1A7), glutathione S-transferases (GSTM5, GSTA2 and GSTP1), and NAD(P)H quinone oxidoreductase (NQO1). The transcription factor NF-E2-related factor-2 (Nrf2), a master regulator of this antioxidant response, is also elevated in IRI. Furthermore, microarray analysis of renal epithelial cells exposed to hypoxia/reoxygenation identified Nrf2 to be up-regulated on reoxygenation. We also reveal a reoxygenation-specific nuclear accumulation of Nrf2 protein and subsequent activation of a NQO1 promoter reporter construct. Attenuating reactive oxygen species (ROS) in reoxygenation using the antioxidant N-acetyl cysteine results in inhibition of Nrf-2 activation. mRNA levels for Nrf2-dependent genes were detected in human liver biopsy 1 h after transplantation. These results indicate that reoxygenation-dependent Nrf-2 activity facilitates ischemic preconditioning through the induction of antioxidant gene expression and that ROS may be critical in signaling this event.—Leonard, M. O., Kieran, N. E., Howell, K., Burne, M. J., Varadarajan, R., Dhakshinamoorthy, S., Porter, A. G., O’Farrelly, C., Rabb, H., Taylor, C. T. Reoxygenation-specific activation of the antioxidant transcription factor Nrf2 mediates cytoprotective gene expression in ischemia reperfusion injury.

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