Crosstalk between and Nrf2 during Recovery from Acute Hemolytic Anemia.

and nuclear factor (erythroid-derived 2)-like 2 () regulate two antioxidative systems that have been identified to maintain redox homeostasis in erythroid cells by removing excess reactive oxygen species (ROS). Whether these two genes coordinate to affect ROS scavenging and the anemic phenotype, or which gene is more important for recovery from acute anemia, has not been explored. To address these questions, we crossed knockout (KO) and KO mice and examined the phenotype change in the animals as well as the ROS levels in erythroid cells either at baseline or under stress condition. Several discoveries were made in this study. First, / double-KO mice unexpectedly exhibit similar anemic phenotypes as single-KO mice during stable erythropoiesis, although compound mutations of and lead to higher ROS levels in erythrocytes than single gene mutations. Second, / double-mutant mice exhibit more dramatic reticulocytosis than or single-KO mice during days 3 to 7 after inducing acute hemolytic anemia using phenylhydrazine (PHZ), indicating a synergistic effect of and Nrf2 on PHZ-induced stress erythropoiesis. However, the coordination does not persist during the whole recovery stage of PHZ-induced anemia; instead, / double-KO mice follow a recovery pattern similar to single-KO mice during the remaining period of erythropoiesis. Third, the complete recovery from PHZ-induced acute anemia in KO mice takes longer than in KO mice. Our findings demonstrate that complicated crosstalk between and Nrf2 does exist and the crosstalk of these two antioxidant systems is development-stage-dependent. Our findings also demonstrate that deficiency could result in a more profound defect of erythropoiesis than dysfunctional transcription factors.