Mice with targeted deletion of <i>Ncoa4</i> specifically in the erythroid compartment developed a pronounced anemia in the immediate postnatal stage, a mild hypochromic microcytic anemia at adult stages, and were more sensitive to hemolysis with higher requirements for the Hif2a-erythropoietin axis and extramedullary erythropoiesis during recovery.
This work indicates that the crosstalk between liver hepcidin and intestinal HIF-2α plays an important role during iron overload, systemic iron deficiency, and anemia.
The authors show that excess iron decreases levels of hypoxia-inducible transcription factor 2α (HIF2α), the main driver of erythropoietin production in hypoxia and anemia.
Taken together, our results demonstrate for the first time that conditional loss of PHD2 in mice leads to HIF-2α-dependent erythrocytosis, whereas HIF-1α protects these mice, providing a platform for developing new treatments of EPO-related disorders, such as anemia.