The circadian clock regulates rhythmic activation of the NRF2/glutathionemediated antioxidant defense pathway to modulate pulmonary fibrosis

Vanja Pekovic-Vaughan, Julie Gibbs, Hikari Yoshitane, Nan Yang, Dharshika Pathiranage, Baoqiang Guo, Aya Sagami, Keiko Taguchi, David Bechtold, Andrew Loudon, Masayuki Yamamoto, Jefferson Chan, Gijsbertus T.J. van der Horst, Yoshitaka Fukada, Qing Jun Meng

Research output: Contribution to journalArticlepeer-review

123 Citations (Scopus)

Abstract

The disruption of the NRF2 (nuclear factor erythroid-derived 2-like 2)/glutathione-mediated antioxidant defense pathway is a critical step in the pathogenesis of several chronic pulmonary diseases and cancer. While the mechanism of NRF2 activation upon oxidative stress has been widely investigated, little is known about the endogenous signals that regulate the NRF2 pathway in lung physiology and pathology. Here we show that an E-box-mediated circadian rhythm of NRF2 protein is essential in regulating the rhythmic expression of antioxidant genes involved in glutathione redox homeostasis in the mouse lung. Using an in vivo bleomycin-induced lung fibrosis model, we reveal a clock "gated" pulmonary response to oxidative injury, with a more severe fibrotic effect when bleomycin was applied at a circadian nadir in NRF2 levels. Timed administration of sulforaphane, an NRF2 activator, significantly blocked this phenotype. Moreover, in the lungs of the arrhythmic ClockΔ19 mice, the levels of NRF2 and the reduced glutathione are constitutively low, associated with increased protein oxidative damage and a spontaneous fibrotic-like pulmonary phenotype. Our findings reveal a pivotal role for the circadian control of the NRF2/glutathione pathway in combating oxidative/fibrotic lung damage, which might prompt new chronotherapeutic strategies for the treatment of human lung diseases, including idiopathic pulmonary fibrosis.

Original languageEnglish
Pages (from-to)548-560
Number of pages13
JournalGenes and Development
Volume28
Issue number6
DOIs
Publication statusPublished - 2014 Mar 15

Keywords

  • Bleomycin
  • Circadian clock
  • Glutathione
  • NRF2
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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