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J Biol Chem. 2015 Sep 25;290(39):23523-7. doi: 10.1074/jbc.C115.681643. Epub 2015 Aug 19.

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

Author information

1
From the Department of Molecular and Integrative Physiology.
2
Department of Pediatrics, and.
3
the Abramson Research Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104.
4
From the Department of Molecular and Integrative Physiology, Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan 48109 and shahy@umich.edu.

Abstract

Sickle cell disease (SCD) is caused by genetic defects in the β-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)-2α is highly activated in the intestine and is essential in iron absorption. Intestinal disruption of HIF-2α protects against tissue iron accumulation in iron overload anemias. However, the role of intestinal HIF-2α in regulating anemia in SCD is currently not known. Here we show that in mouse models of SCD, disruption of intestinal HIF-2α 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-2α 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-2α disruption. These data suggest that targeting intestinal HIF-2α has a significant therapeutic potential in SCD pathophysiology.

KEYWORDS:

HIF-2α; anemia; hypoxia; hypoxia-inducible factor (HIF); intestinal epithelium; iron; iron homeostasis; iron metabolism; sickle cell disease

PMID:
26296885
PMCID:
PMC4583015
DOI:
10.1074/jbc.C115.681643
[Indexed for MEDLINE]
Free PMC Article

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