TY - JOUR
T1 - Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model
AU - Zhu, Xingguo
AU - Xi, Caixia
AU - Thomas, Bobby
AU - Pace, Betty S.
N1 - Publisher Copyright:
© 2018 by The American Society of Hematology.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041325188&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041325188&partnerID=8YFLogxK
U2 - 10.1182/blood-2017-10-810531
DO - 10.1182/blood-2017-10-810531
M3 - Article
C2 - 29255069
AN - SCOPUS:85041325188
SN - 0006-4971
VL - 131
SP - 558
EP - 562
JO - Blood
JF - Blood
IS - 5
ER -