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Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia

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Abstract

Exposure to high altitude (and thus hypobaric hypoxia) induces electrophysiological, metabolic, and morphological modifications in the brain leading to several neurological clinical syndromes. Despite the known fact that hypoxia episodes in brain are a common factor for many neuropathologies, limited information is available on the underlying cellular and molecular mechanisms. In this study, we investigated the temporal effect of short-term (0–12 h) chronic hypobaric hypoxia on global gene expression of rat brain followed by detailed canonical pathway analysis and regulatory network identification. Our analysis revealed significant alteration of 33, 17, 53, 81, and 296 genes (p < 0.05, <1.5-fold) after 0.5, 1, 3, 6, and 12 h of hypoxia, respectively. Biological processes like regulation, metabolic, and transport pathways are temporally activated along with anti- and proinflammatory signaling networks like PI3K/AKT, NF-κB, ERK/MAPK, IL-6 and IL-8 signaling. Irrespective of exposure durations, nuclear factor (erythroid-derived 2)-like 2 (NRF2)-mediated oxidative stress response pathway and genes were detected at all time points suggesting activation of NRF2-ARE antioxidant defense system. The results were further validated by assessing the expression levels of selected genes in temporal as well as brain regions with quantitative RT-PCR and western blot. In conclusion, our whole brain approach with temporal monitoring of gene expression patterns during hypobaric hypoxia has resulted in (1) deciphering sequence of pathways and signaling networks activated during onset of hypoxia, and (2) elucidation of NRF2-orchestrated antioxidant response as a major intrinsic defense mechanism. The results of this study will aid in better understanding and management of hypoxia-induced brain pathologies.

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Acknowledgment

This study was supported by Defence Institute of Physiology and Allied Sciences Grant TC/297/TASK-122(NKS)/DIPAS/2007. MS is a recipient of Defence Research and Development Organisation (DRDO) Senior Research Fellowship (SRF). The technical support provided by Dr. Dhananjay Shukla is greatly appreciated. The authors declare no conflict of interest.

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  1. Peptide and Proteomics Division, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi, 110054, India

    Niroj Kumar Sethy, Manjulata Singh, Rajesh Kumar, Govindasamy Ilavazhagan & Kalpana Bhargava

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  1. Niroj Kumar Sethy
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  2. Manjulata Singh
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  3. Rajesh Kumar
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  4. Govindasamy Ilavazhagan
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  5. Kalpana Bhargava
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Correspondence to Niroj Kumar Sethy or Kalpana Bhargava.

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Sethy, N.K., Singh, M., Kumar, R. et al. Upregulation of transcription factor NRF2-mediated oxidative stress response pathway in rat brain under short-term chronic hypobaric hypoxia. Funct Integr Genomics 11, 119–137 (2011). https://doi.org/10.1007/s10142-010-0195-y

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  • DOI: https://doi.org/10.1007/s10142-010-0195-y

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