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

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Abstract

The basic leucine zipper transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) 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/NRF22/2) 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 embryonic day 13.5 and embryonic day 18.5 fetal liver and adult spleen and bone marrow cells, respectively. Examination of peripheral red blood cells revealed an increase of reactive oxygen species (ROS) and sickling under hypoxic conditions. Loss of NRF2 function in SCD/NRF22/2 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 ROS, proinflammatory cytokines, and adhesion molecules in SCD mice. Genetic knockout of NRF2 demonstrates its role in developmentally regulated g-globin gene expression and the ability to control oxidative stress and the phenotypic severity of SCD.

Original languageEnglish (US)
Pages (from-to)558-562
Number of pages5
JournalBlood
Volume131
Issue number5
DOIs
StatePublished - Feb 1 2018

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Sickle Cell Anemia
Transgenic Mice
Fetal Hemoglobin
Oxidative stress
Reactive Oxygen Species
Oxidative Stress
Antioxidants
Cells
Basic-Leucine Zipper Transcription Factors
Globins
Erythropoiesis
Splenomegaly
Gene expression
Bone Marrow Cells
Liver
Pulp
Bone
Blood
Adhesion
Spleen

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model. / Zhu, Xingguo; Xi, Caixia; Thomas, Bobby; Pace, Betty S.

In: Blood, Vol. 131, No. 5, 01.02.2018, p. 558-562.

Research output: Contribution to journalArticle

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