Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)

Peyssonnaux, Carole; Zinkernagel, Annelies S.; Schuepbach, Reto A.; Rankin, Erinn B.; Vaulont, Sophie; Haase, Volker H.; Nizet, Victor; Johnson, Randall S.

doi:10.1172/jci31370

Cited by 564 publications

(487 citation statements)

References 33 publications

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“…35 In basal conditions, HJV, as a cleaved heterodimer, reaches the plasma membrane and acts as a BMP coreceptor to activate hepcidin, when diferric transferrin increases. 12 Hypoxia directly 17 and iron deficiency indirectly (by stabilizing HIF-1␣) 22,23 activate furin to release s-HJV, in order to interfere with BMP signaling and to inhibit hepcidin activation.…”

Section: Discussionmentioning

confidence: 99%

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Silvestri

Pagani

Camaschella

2008

Blood

275

276

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The liver peptide hepcidin regulates iron absorption and recycling. Hemojuvelin (HJV) has a key role in hepcidin regulation, and its inactivation causes severe iron overload both in humans and in mice. Membrane HJV (m-HJV) acts as a coreceptor for bone morphogenetic proteins (BMPs), whereas soluble HJV (s-HJV) may down-regulate hepcidin in a competitive way interfering with BMP signaling. s-HJV is decreased by iron in vitro and increased by iron deficiency in vivo. IntroductionThe liver peptide hepcidin is the key regulator of systemic iron homeostasis 1 since it determines the level of circulating iron controlling intestinal iron absorption and macrophage iron recycling. Hemojuvelin (HJV) is a recently recognized protein that plays a crucial role in the regulation of hepcidin. The HJV gene, encoding HJV, is the gene of 1q-linked juvenile hemochromatosis, a recessive disease that leads to severe iron overload of early onset (hemochromatosis type 2A, OMIM no. 602390). 2 Patients with mutated HJV as well as Hjv Ϫ/Ϫ mice 3,4 have low/absent hepcidin levels, indicating that HJV modulates hepcidin. HJV is expressed in liver, skeletal muscle, and heart 2 and belongs to the family of repulsive guidance molecules (RGMs), expressed mainly in the central nervous system. 5,6 As are the other RGM proteins, HJV is characterized by a signal peptide, a RGD motif, a partial von Willebrand factor type D domain, and a glycosilphosphatidylinositol (GPI)-anchor domain. 2 HJV undergoes a partial autocatalytic cleavage 7 to reach the plasma membrane (m-HJV) as a cleaved heterodimer. 8,9 Recently, it was shown that HJV is a coreceptor for bone morphogenetic proteins (BMPs) and that hepcidin regulation occurs via the BMP/SMAD pathway. 10,11 BMP2 and BMP4 signaling is dependent on diferric transferrin, thus establishing a link between HJV-BMP and iron. 12 HJV exists in 2 forms: a membrane-bound (m-HJV) and a soluble one (s-HJV), which in vitro reciprocally regulate hepcidin expression in response to opposite iron changes. 7 s-HJV is able to interfere with and to block the signaling of BMP2 and BMP4 both in vitro 12 and in vivo. 13 We have previously documented the relevance of m-HJV in the molecular pathogenesis of juvenile hemochromatosis, providing evidence that at least some of the mutants identified as causal in patients are less efficiently targeted to the plasma membrane, compared with the wild-type protein. 9 Generation of s-HJV appears to be a regulated process decreased by iron treatment and diferric transferrin. 7 During our previous study, we have confirmed that this regulation is maintained in mutants, strengthening that s-HJV, suppressed by iron overload, is not involved in the disease pathogenesis. 9 We have also suggested that s-HJV does not derive from shedding of m-HJV, since its release in the medium is observed even in mutants that barely reach the plasma membrane. The discrepancy between the presence of m-HJV and the production of s-HJV is also well exemplified by the efficient secretion of soluble forms from varian...

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Section: Discussionmentioning

confidence: 99%

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Silvestri

Pagani

Camaschella

2008

Blood

275

276

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“…Hypoxia is a main regulator of iron homeostasis as it strongly down-regulates hepcidin [32], likely through a mechanism involving both HIF1α and HIF2α [33]. It is intriguing that the same stimulus may both inhibit hepcidin expression and induce its target protein, FPN, in duodenum and macrophages, thus ensuring an adequate iron supply for erythropoiesis.…”

Section: Discussionmentioning

confidence: 99%

Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice

Chiabrando

Fiorito

Marro

et al. 2013

Blood Cells, Molecules, and Diseases

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Here we show that, during experimentally-induced acute anemia in mice, FPN is regulated at transcriptional level in a cell-specific manner. FPN mRNA level increases in duodenum and spleen macrophages, whereas it does not change in liver and is strongly down-regulated in erythroid precursors. These results were confirmed in Caco2 Raw264.7 and K562 cells treated with a hypoxic stimulus. Moreover, we found a differential expression of HIF1α and HIF2α in cells and tissues that might account for the specificity of FPN regulation.Thus, hypoxia, by directly controlling hepcidin and its target FPN, orchestrates a complex regulatory network aimed at ensuring rapid iron recovery from the periphery and efficient iron utilization in the erythroid compartment.

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“…Furthermore, HIF activation influences genes that play important roles in iron metabolism, including transferrin [15], ferroportin [16], and possibly hepcidin [16]. Thus, in addition to increased EPO expression, HIF regulates various pathways leading to efficient erythropoiesis [16].…”

Section: Mechanisms Of Renal Erythropoietin Productionmentioning

confidence: 99%

“…Thus, in addition to increased EPO expression, HIF regulates various pathways leading to efficient erythropoiesis [16].…”

Section: Mechanisms Of Renal Erythropoietin Productionmentioning

confidence: 99%

Hypoxia and the HIF system in kidney disease

2007

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The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive β-subunit and one of alternative oxygen-regulated HIF α-subunits (HIF-1α, HIF-2α, and HIF-3α), and HIF-2α is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

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Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs)

Cited by 564 publications

References 33 publications

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis

Cell-specific regulation of Ferroportin transcription following experimentally-induced acute anemia in mice

Hypoxia and the HIF system in kidney disease

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