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. 2012 Jun;97(6):827-34.
doi: 10.3324/haematol.2011.056119. Epub 2011 Dec 29.

VSports最新版本 - Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis

Maria Mastrogiannaki  1 , Pavle Matak, Jacques R R Mathieu, Stéphanie Delga, Patrick Mayeux, Sophie Vaulont, Carole Peyssonnaux
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"V体育官网入口" Hepatic hypoxia-inducible factor-2 down-regulates hepcidin expression in mice through an erythropoietin-mediated increase in erythropoiesis

Maria Mastrogiannaki et al. Haematologica. 2012 Jun.

Abstract

Background: Iron metabolism, regulated by the iron hormone hepcidin, and oxygen homeostasis, dependent on hypoxia-inducible factors, are strongly interconnected VSports手机版. We previously reported that in mice in which both liver hypoxia-inducible factors-1 and -2 are stabilized (the hepatocyte von Hippel-Lindau knockout mouse model), hepcidin expression was strongly repressed and we hypothesized that hypoxia-inducible factor-2 could be the major regulatory component contributing to the hepcidin down-regulation. .

Design and methods: We generated and analyzed hepatocyte-specific knockout mice harboring either hypoxia-inducible factor-2α deficiency (Hif2a knockout) or constitutive hypoxia-inducible factor-2α stabilization (Vhlh/Hif1a knockout) and ex vivo systems (primary hepatocyte cultures). Hif2a knockout mice were fed an iron-deficient diet for 2 months and Vhlh/Hif1a knockout mice were treated with neutralizing erythropoietin antibody. V体育安卓版.

Results: We demonstrated that hypoxia-inducible factor-2 is dispensable in hepcidin gene regulation in the context of an adaptive response to iron-deficiency anemia. However, its overexpression in the double Vhlh/Hif1a hepatocyte-specific knockout mice indirectly down-regulates hepcidin expression through increased erythropoiesis and erythropoietin production. Experiments in primary hepatocytes confirmed the non-autonomous role of hypoxia-inducible factor-2 in hepcidin regulation. V体育ios版.

Conclusions: While our results indicate that hypoxia-inducible factor-2 is not directly involved in hepcidin repression, they highlight the contribution of hepatic hypoxia-inducible factor-2 to the repression of hepcidin through erythropoietin-mediated increased erythropoiesis, a result of potential clinical interest. VSports最新版本.

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Figures

Figure 1.
Figure 1.
Mice with HIF2-α-deficient liver respond normally to diet-induced iron deficiency. Hif2alox/loxAlbumin Cre-and Hif2alox/loxAlbumin Cre+ littermates were fed an iron deficient (-Fe diet) or control diet (Ctr) for 2 months after weaning. (A) Hepatic hepcidin and renal erythropoietin (EPO) relative mRNA expression normalized to cyclophilin-A mRNA. Results are expressed as a fold change compared to the Hif2alox/loxAlbumin Cre-mice on a control diet. EPO in plasma of WT and Hif2alox/loxAlbumin Cre+ mice fed an iron deficient or control diet. (B) Hematologic parameters. (C) Liver and plasma iron contents. n ≥ 4 for each group.
Figure 2.
Figure 2.
Characterization of Vhlhlox/loxHif1alox/loxAlbumin Cre+ mice. (A) Body, spleen and liver weight of Vhlhlox/lox Hif1alox/loxAlbumin Cre+ (KO) and control mice (Ctr). n = 4. Plasma iron in Vhlhlox/lox Hif1alox/loxAlbumin Cre+ (KO) and control mice (Ctr). n=5. (B) Relative mRNA expression normalized to cyclophilin-A mRNA in the liver of Vhlhlox/lox Hif1alox/loxAlbumin Cre+ compared to Ctr. Ctr: n=9; KO : n=8. (C) Hepatic and renal erythropoietin mRNA (Ctr : n=11; KO : n=6) and plasma erythropoietin levels in Vhlhlox/loxHif1alox/loxAlbumin Cre+ (KO) compared with levels in control lit-termates (Ctr). Ctr: n=31; KO: n=14. (D) Hemoglobin and reticulocyte counts in Vhlhlox/lox Hif1alox/loxAlbumin Cre+ (KO) and control mice (Ctr). n ≥ 3 for each group.
Figure 3.
Figure 3.
Inhibition of erythropoietic activity in Vhlhlox/loxHif1alox/loxAlbumin Cre+ mice normalizes liver hepcidin expression. Mice were injected every day with 300 μL NaCl or rabbit anti-erythropoietin serum (a-EPO) for 5 days and sacrificed 16 h after the last injection. (A) Reticulocytes, red blood cells, hemoglobin and hematocrit counts. (B) Relative hepcidin mRNA expression in the liver expressed as a fold difference compared with that in NaCl injected control (Ctr) mice. Ctr: NaCl (n=10), Ctr: Anti-EPO (n=9), KO: NaCl (n=3), KO: Anti-EPO (n=5)
Figure 4.
Figure 4.
HIF-2α overexpression does not repress hepcidin expression in primary hepatocytes. Infection of wild-type primary hepatocytes with a control GFP-adenovirus (AV-GFP) (black bar) or with a HIF2-α-overexpressing adenovirus (AV-HIF-2α) (gray bar) at a multiplicity of infection (MOI) of 10. Relative mRNA expression normalized to cyclophilin-A. Representation of three independent experiments performed in triplicate.
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References

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    1. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–54. - PMC - PubMed
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