Deficiency of heme-regulated eIF2alpha kinase decreases hepcidin expression and splenic iron in HFE-/- mice

Abstract

Heme-regulated eIF2alpha kinase (HRI) is essential for regulating globin translation in iron deficiency and in beta-thalassemia. We investigated the role of heme-regulated eIF2alpha kinase in hemoglobin and red blood cell production as well as in iron homeostasis in a mouse model of iron overload. We show that HRI deficiency does not significantly affect red cell parameters of hemochromatosis (HFE(-)(/)(-)) mice. Importantly, heme-regulated eIF2alpha kinase deficiency exacerbates decreases in hepcidin expression and splenic macrophage iron in HFE(-)(/)(-) mice. Furthermore, the serum level of bone morphogenic protein 2, which positively regulates hepcidin, is reduced in heme-regulated eIF2alpha kinase deficiency, but not in HFE deficiency.

Figure 1

Effects of HRI on the tissue and serum iron contents in HFE^−/− mice. (A) Hepatic iron contents, (B) Splenic iron contents, (C) Iron stain of spleen tissue sections (D) Serum iron contents. Results are presented as mean±SEM (n=7–9).

Figure 2

Effects of HRI, HFE and iron on hepatic hepcidin expression and serum BMP2 levels. (A) Hepatic hepcidin mRNA expression. (B) Serum BMP2 levels. Hepcidin mRNA expression was analyzed by qRT-PCR and normalized with eIF2α. Hepcidin expression in Wt is defined as 1. Results are presented as mean±SEM (n=7–9).