Intestine-specific Disruption of Hypoxia-inducible Factor (HIF)-2α Improves Anemia in Sickle Cell Disease

Sickle cell disease (SCD) is caused by genetic defects in the beta-globin chain. SCD is a frequently inherited blood disorder, and sickle cell anemia is a common type of hemoglobinopathy. During anemia, the hypoxic response via the transcription factor hypoxia-inducible factor (HIF)-2 alpha is highly activated in the intestine and is essential in iron absorption. Intestinal disruption of HIF-2 alpha protects against tissue iron accumulation in iron overload anemias. However, the role of intestinal HIF-2 alpha in regulating anemia in SCD is currently not known. Here we show that in mouse models of SCD, disruption of intestinal HIF-2 alpha significantly decreased tissue iron accumulation. This was attributed to a decrease in intestinal iron absorptive genes, which were highly induced in a mouse model of SCD. Interestingly, disruption of intestinal HIF-2 alpha led to a robust improvement in anemia with an increase in RBC, hemoglobin, and hematocrit. This was attributed to improvement in RBC survival, hemolysis, and insufficient erythropoiesis, which is evident from a significant decrease in serum bilirubin, reticulocyte counts, and serum erythropoietin following intestinal HIF-2 alpha disruption. These data suggest that targeting intestinal HIF-2 alpha has a significant therapeutic potential in SCD pathophysiology.