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Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model

Xingguo Zhu, Caixia Xi, Bobby Thomas and Betty S. Pace

Key points

  • NRF2 knockout inhibits fetal hemoglobin expression during gestational erythropoiesis in sickle cell disease mice.

  • Loss of the cellular antioxidant response mediated by NRF2 exacerbates spleen damage, inflammation, and oxidative stress in SCD mice.

Abstract

The basic leucine zipper transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) plays a critical role in the cellular antioxidant response under oxidative stress conditions. In this study, we investigated the role of NRF2 in fetal hemoglobin expression and the pathophysiology of sickle cell disease (SCD) in a NRF2 knockout (SCD/NRF2-/-) transgenic mouse model. NRF2 loss impaired survival of SCD pups during gestation and in the first 2 months of life. Furthermore, fetal hemoglobin expression was inhibited during erythropoiesis in E13.5 and E18.5 embryonic fetal liver, and adult spleen and bone marrow cells respectively. Examination of peripheral red blood cells revealed an increase of reactive oxygen species and sickling under hypoxic conditions. Loss of NRF2 function in SCD/NRF2-/- mice produced greater splenomegaly with red pulp expansion and obscured architecture. In addition, NRF2 knockout reduced the expression of its target antioxidant proteins leading to increased levels of reactive oxygen species, pro-inflammatory cytokines and adhesion molecules in SCD mice. Genetic knockout of NRF2 demonstrates its role in developmentally regulated γ-globin gene expression and ability to control oxidative stress and the phenotypic severity of SCD.

  • Submitted October 11, 2017.
  • Accepted December 5, 2017.