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Cited by 787Erythropoietin and Anemia TreatmentHigh Altitude and HypoxiaCancer, Hypoxia, and Metabolism

Regulation of erythropoiesis by hypoxia-inducible factors

Open access
Haase, Volker H.·2013·Blood Reviews
DOI 10.1016/j.blre.2012.12.003PMC PMC3731139
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Abstract

A classic physiologic response to systemic hypoxia is the increase in red blood cell production. Hypoxia-inducible factors (HIFs) orchestrate this response by inducing cell-type specific gene expression changes that result in increased erythropoietin (EPO) production in kidney and liver, in enhanced iron uptake and utilization and in adjustments of the bone marrow microenvironment that facilitate erythroid progenitor maturation and proliferation. In particular HIF-2 has emerged as the transcription factor that regulates EPO synthesis in the kidney and liver and plays a critical role in the regulation of intestinal iron uptake. Its key function in the hypoxic regulation of erythropoiesis is underscored by genetic studies in human populations that live at high-altitude and by mutational analysis of patients with familial erythrocytosis. This review provides a perspective on recent insights into HIF-controlled erythropoiesis and iron metabolism, and examines cell types that have EPO-producing capability. Furthermore, the review summarizes clinical syndromes associated with mutations in the O2-sensing pathway and the genetic changes that occur in high altitude natives. The therapeutic potential of pharmacologic HIF activation for the treatment of anemia is discussed.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that HIF-2, rather than HIF-1, is the central transcription factor controlling adult renal and hepatic erythropoietin production, intestinal iron uptake, and coordination of erythropoiesis with iron metabolism. It also discusses HIF-pathway mutations in erythrocytosis, high-altitude adaptation, and pharmacologic HIF activation as a potential anemia therapy.

Key findings

  • HIF-2 is the main regulator of EPO synthesis in adult kidney and liver: renal and hepatic EPO responses are HIF-2-dependent, whereas HIF-1 does not play a significant role in systemic EPO homeostasis at baseline or after acute anemia.
  • HIF-2 directly regulates intestinal iron uptake genes DMT1 and DCYTB, while hepcidin suppression under hypoxia/hepatic HIF activation is indirect and requires EPO-mediated erythropoietic activity in the bone marrow.
  • Human HIF-pathway mutations cause secondary erythrocytosis: Chuvash polycythemia is caused by homozygous VHL R200W; HIF2A gain-of-function mutations cluster near proline 531; PHD2 mutations reduce hydroxylase activity.
  • High-altitude adaptation involves HIF2A, PHD2, and PPARA variants; native Tibetan males had lower hemoglobin concentrations than Andean males (15.6 g/dL vs. 19.2 g/dL), and CMS is defined by excessive erythrocytosis (females Hgb ≥19 g/dL; males Hgb ≥21 g/dL).
  • Pharmacologic PHD inhibition increases serum EPO and has therapeutic potential for anemia, but PHD1/PHD3 double-knockout mice showed only mild-to-moderate erythrocytosis (Hct 67% vs. 53% in controls), whereas global PHD2 deletion caused severe erythrocytosis (Hct >80%).

Methods

  • Narrative review of experimental and clinical literature on HIF regulation of erythropoiesis, iron metabolism, erythrocytosis syndromes, high-altitude adaptation, and anemia therapeutics.
  • Synthesizes evidence from cell culture, mouse genetic models, human mutational analyses, and high-altitude population studies; no primary data collection or systematic search strategy is reported.
  • Main analysis is qualitative synthesis of mechanisms and clinical implications, not a meta-analysis or systematic review.

Limitations

  • The paper states several unresolved issues: mechanisms underlying loss of EPO-producing ability in CKD are unclear; the degree of overlap between renal EPO-producing cells and myofibroblasts remains to be determined; specific factors required for HIF-2-dependent EPO induction have not yet been identified; the role of sirtuins needs further study; and whether tissue-specific PHD targeting is as efficacious as systemic therapy remains to be investigated.
  • The paper states that long-term effects of HIF-stabilizing compounds on glucose, fat, cholesterol metabolism, angiogenesis, and other processes require careful evaluation in clinical trials and controlled physiologic studies.
  • Evident from the text: as a narrative review, it lacks a systematic search, inclusion criteria, risk-of-bias assessment, and quantitative synthesis, so conclusions may reflect selective citation of the literature.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.blre.2012.12.003

Cites

258 of 258 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 225 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Hepcidin suppression under conditions of hypoxia and hepatic HIF activation is dependent on erythropoietic activity in the bone marrow.

    “Hepcidin suppression under conditions of hypoxia and hepatic HIF activation was dependent on erythropoietic activity in the bone marrow.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Liu Q Davidoff O Niss K Haase VH Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis J Clin Invest 2012 122 4635 44 23114598 PMC3533545 source

      Not checked in the free run.

  • Findingcitation

    Studies in humans receiving recombinant EPO have not yet shown a significant inverse relationship between serum hepcidin and GDF15 levels.

    “studies in humans receiving recombinant EPO have not yet shown a significant inverse relationship between serum hepcidin and GDF15 levels”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [208] Liu Q Davidoff O Niss K Haase VH Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis J Clin Invest 2012 122 4635 44 23114598 PMC3533545 source

      Not checked in the free run.

    • cites [222] Ashby DR Gale DP Busbridge M Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin Haematologica 2009 95 505 8 19833632 PMC2833083 source

      Not checked in the free run.

  • Findingown data

    Induction of EPO synthesis alone is not sufficient to suppress hepcidin in the conditional knockout model.

    “However, we determined that the induction of EPO synthesis alone was not sufficient to suppress hepcidin in this model.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Liu Q Davidoff O Niss K Haase VH Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis J Clin Invest 2012 122 4635 44 23114598 PMC3533545 source

      Not checked in the free run.

  • Findingown data

    Hypoxia/HIF-mediated suppression of hepcidin requires EPO.

    “found that hypoxia/HIF-mediated suppression of hepcidin required EPO.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [208] Liu Q Davidoff O Niss K Haase VH Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis J Clin Invest 2012 122 4635 44 23114598 PMC3533545 source

      Not checked in the free run.

  • Findingcitation

    Recombinant murine GDF15 suppressed hepcidin in Hep3B cells at a concentration of 750 pg/ml.

    “We found that recombinant murine GDF15 suppressed hepcidin in Hep3B cells at a concentration of 750 pg/ml.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [208] Liu Q Davidoff O Niss K Haase VH Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis J Clin Invest 2012 122 4635 44 23114598 PMC3533545 source

      Not checked in the free run.

  • May combine two claims. 45
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Under hypoxia, hydroxylation is inhibited and HIF signaling is activated.

    “Under hypoxia, hydroxylation is inhibited and HIF signaling is activated. 86”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Kaelin WG Jr Ratcliffe PJ Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway Mol Cell 2008 30 393 402 18498744 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF is a heterodimeric bHLH PAS transcription factor consisting of an O2-sensitive α-subunit and a constitutively expressed β-subunit, ARNT.

    “It consists of an O2-sensitive α-subunit and a constitutively expressed β-subunit, also known as the aryl hydrocarbon receptor nuclear translocator (ARNT). 57–59”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [57] Kewley RJ Whitelaw ML Chapman-Smith A The mammalian basic helix-loop-helix/PAS family of transcriptional regulators Int J Biochem Cell Biol 2004 36 189 204 14643885

      Not checked in the free run.

    • cites [58] Semenza GL Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1 Annu Rev Cell Dev Biol 1999 15 551 78 10611972 source

      Not checked in the free run.

    • cites [59] Wenger RH Stiehl DP Camenisch G Integration of oxygen signaling at the consensus HRE Sci STKE 2005 2005 re12 16234508

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    O2-dependent Epo transcription is controlled by a kidney-inducibility element in the 5′-region and a liver-inducibility element in the 3′-region.

    “O2-dependent Epo transcription is controlled by distinct regulatory DNA sequences. These flank the Epo coding sequence on both sides, the kidney-inducibility element in the 5′-region and the liver-inducibility element in the 3′-region. 15–17”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Semenza GL Traystman MD Gearhart JD Antonarakis SE Polycythemia in transgenic mice expressing the human erythropoietin gene Proc Natl Acad Sci U S A 1989 86 2301 5 2928334 PMC286900

      Not checked in the free run.

    • cites [16] Semenza GL Koury ST Nejfelt MK Gearhart JD Antonarakis SE Cell-type-specific and hypoxia-inducible expression of the human erythropoietin gene in transgenic mice Proc Natl Acad Sci U S A 1991 88 8725 9 1924331 PMC52582

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    • cites [17] Semenza GL Dureza RC Traystman MD Gearhart JD Antonarakis SE Human erythropoietin gene expression in transgenic mice: multiple transcription initiation sites and cis-acting regulatory elements Mol Cell Biol 1990 10 930 8 2304468 PMC360936

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    HIF promotes erythropoiesis at multiple levels and coordinates cell type-specific hypoxia responses.

    “Recent experimental data indicate that HIF promotes erythropoiesis at multiple levels and coordinates cell type-specific hypoxia responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    EPO production is primarily stimulated by hypoxia, which increases serum EPO levels up to several hundred-fold depending on severity.

    “EPO production is primarily stimulated by hypoxia, which, depending on severity, increases serum EPO levels up to several hundred-fold. 56”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Ebert BL Bunn HF Regulation of the erythropoietin gene Blood 1999 94 1864 77 10477715

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EPO is produced by peritubular interstitial fibroblasts and not by renal tubular epithelial cells or peritubular endothelial cells.

    “Although initially debated, EPO is produced by peritubular interstitial fibroblasts and not by renal tubular epithelial cells or peritubular endothelial cells. 6–12”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [6] Lacombe C Da Silva JL Bruneval P Peritubular cells are the site of erythropoietin synthesis in the murine hypoxic kidney J Clin Invest 1988 81 620 3 3339134 PMC329613

      Not checked in the free run.

    • cites [7] Koury ST Bondurant MC Koury MJ Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization Blood 1988 71 524 7 3337914

      Not checked in the free run.

    • cites [8] Koury ST Koury MJ Bondurant MC Caro J Graber SE Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration Blood 1989 74 645 51 2752138

      Not checked in the free run.

    • cites [9] Bachmann S Le Hir M Eckardt KU Co-localization of erythropoietin mRNA and ecto-5′-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin J Histochem Cytochem 1993 41 335 41 8429197

      Not checked in the free run.

    • cites [10] Maxwell PH Osmond MK Pugh CW Identification of the renal erythropoietin-producing cells using transgenic mice Kidney Int 1993 44 1149 62 8264149

      Not checked in the free run.

    • cites [11] Obara N Suzuki N Kim K Nagasawa T Imagawa S Yamamoto M Repression via the GATA box is essential for tissue-specific erythropoietin gene expression Blood 2008 111 5223 32 18202227

      Not checked in the free run.

    • cites [12] Paliege A Rosenberger C Bondke A Hypoxia-inducible factor-2alpha-expressing interstitial fibroblasts are the only renal cells that express erythropoietin under hypoxia-inducible factor stabilization Kidney Int 2010 77 312 8 20016470

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anaerobic glycolysis is predominantly controlled by HIF-1, whereas EPO synthesis and iron metabolism are HIF-2-regulated processes.

    “For example, anaerobic glycolysis appears to be predominantly controlled by HIF-1, 68 whereas EPO synthesis and iron metabolism have emerged as HIF-2-regulated processes. 24, 69–73”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [68] Hu CJ Wang LY Chodosh LA Keith B Simon MC Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation Mol Cell Biol 2003 23 9361 74 14645546 PMC309606 source

      Not checked in the free run.

    • cites [24] Kapitsinou PP Liu Q Unger TL Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia Blood 2010 116 3039 48 20628150 PMC2974609

      Not checked in the free run.

    • cites [69] Morita M Ohneda O Yamashita T HLF/HIF-2alpha is a key factor in retinopathy of prematurity in association with erythropoietin Embo J 2003 22 1134 46 12606578 PMC150350

      Not checked in the free run.

    • cites [70] Scortegagna M Ding K Zhang Q HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner Blood 2005 105 3133 40 15626745

      Not checked in the free run.

    • cites [71] Gruber M Hu CJ Johnson RS Brown EJ Keith B Simon MC Acute postnatal ablation of Hif-2alpha results in anemia Proc Natl Acad Sci U S A 2007 104 2301 6 17284606 PMC1892942

      Not checked in the free run.

    • cites [72] Rankin EB Biju MP Liu Q Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo J Clin Invest 2007 117 1068 77 17404621 PMC1838939

      Not checked in the free run.

    • cites [73] Mastrogiannaki M Matak P Keith B Simon MC Vaulont S Peyssonnaux C HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice J Clin Invest 2009 119 1159 66 19352007 PMC2673882 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Renal and liver EPO synthesis is HIF-2- and not HIF-1-dependent.

    “genetic studies in mice have demonstrated that renal and liver EPO synthesis is HIF-2- and not HIF-1-dependent, as did siRNA and chromatin immunoprecipitation (ChIP)-based studies in certain EPO-producing cell lines; 72, 99, 100”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [72] Rankin EB Biju MP Liu Q Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo J Clin Invest 2007 117 1068 77 17404621 PMC1838939

      Not checked in the free run.

    • cites [99] Warnecke C Zaborowska Z Kurreck J Differentiating the functional role of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha (EPAS-1) by the use of RNA interference: erythropoietin is a HIF-2alpha target gene in Hep3B and Kelly cells Faseb J 2004 18 1462 4 15240563

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    • cites [100] Chavez JC Baranova O Lin J Pichiule P The transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes J Neurosci 2006 26 9471 81 16971531 PMC6674587

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The kidney responds to hypoxia by increasing the number of REPC in an O2-dependent manner and regulates EPO output through adjustments in REPC number.

    “The kidney responds to hypoxia by increasing the number of REPC in an O2-dependent manner and therefore regulates EPO output through adjustments in REPC number. 8, 11”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Koury ST Koury MJ Bondurant MC Caro J Graber SE Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration Blood 1989 74 645 51 2752138

      Not checked in the free run.

    • cites [11] Obara N Suzuki N Kim K Nagasawa T Imagawa S Yamamoto M Repression via the GATA box is essential for tissue-specific erythropoietin gene expression Blood 2008 111 5223 32 18202227

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the adult liver, Epo mRNA levels rise substantially under moderate to severe hypoxia and account for most, if not all, physiologically relevant systemic EPO of extra-renal origin.

    “In the adult liver, Epo mRNA levels, which are very difficult to detect at baseline, rise substantially under conditions of moderate to severe hypoxia, and account for most, if not all, physiologically relevant systemic EPO of extra-renal origin. 23, 33”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Fried W The liver as a source of extrarenal erythropoietin production Blood 1972 40 671 7 4637502

      Not checked in the free run.

    • cites [33] Fried W Kilbridge T Krantz S McDonald TP Lange RD Studies on extrarenal erythropoietin J Lab Clin Med 1969 73 244 8 5764021

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Anemia in HIF-2 knockout mice was due to inadequate renal EPO production, indicating that HIF-2 is indispensable for systemic EPO homeostasis in adults.

    “Further analysis revealed that anemia in these mice did not result from a cell-autonomous defect in erythroid precursor maturation, but was due to inadequate renal EPO production, indicating that HIF-2 was indispensable for systemic EPO homoeostasis in adults. 70”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Scortegagna M Ding K Zhang Q HIF-2alpha regulates murine hematopoietic development in an erythropoietin-dependent manner Blood 2005 105 3133 40 15626745

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Over-expression of non-degradable HIF-2α in hepatocytes produced erythrocytosis, whereas over-expression of HIF-1α did not.

    “Over-expression of non-degradable HIF-2α in hepatocytes produced erythrocytosis, whereas over-expression of HIF-1α did not. 110”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [110] Kim WY Safran M Buckley MR Failure to prolyl hydroxylate hypoxia-inducible factor alpha phenocopies VHL inactivation in vivo Embo J 2006 25 4650 62 16977322 PMC1589988 source

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  • May combine two claims.

    Interpretationreasoning

    Mutations in HIF-1α have not been described in idiopathic erythrocytosis, underscoring the importance of HIF-2 in the regulation of EPO synthesis in humans.

    “Interestingly, mutations in HIF-1α have not been described to date, underscoring the importance of HIF-2 in the regulation of EPO synthesis in humans.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HIF-2α is acetylated during hypoxia and de-acetylated by Sirtuin 1, which increases HIF-2-dependent EPO synthesis in vitro and in vivo.

    “HIF-2α is acetylated during hypoxia and de-acetylated by Sirtuin 1, a nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylase, which increases HIF-2-dependent EPO synthesis in vitro and in vivo”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [114] Dioum EM Chen R Alexander MS Regulation of hypoxia-inducible factor 2alpha signaling by the stress-responsive deacetylase sirtuin 1 Science 2009 324 1289 93 19498162

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF-2 knockout mice were pancytopenic and displayed a hypocellular bone marrow.

    “Furthermore, HIF-2 knockout mice were pancytopenic and displayed a hypocellular bone marrow. 108”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] Scortegagna M Morris MA Oktay Y Bennett M Garcia JA The HIF family member EPAS1/HIF-2alpha is required for normal hematopoiesis in mice Blood 2003 102 1634 40 12750163

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Hepcidin is a critical O2-sensitive regulator of systemic iron homeostasis, mainly produced by hepatocytes, where its transcription is iron- and O2-sensitive.

    “A critical O2-sensitive regulator of systemic iron homeostasis that has received much attention is hepcidin, a small 25 amino acid containing peptide, which is mainly produced by hepatocytes, where its transcription is iron- and O2-sensitive.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The identified HIF2A, PHD2 and PPARA alleles are predicted to confer adaptation to the hypoxic environment and to modulate susceptibility to CMS and other high altitude-associated diseases.

    “Although the precise biological function of these alleles is not known, they are predicted to confer adaptation to the hypoxic environment and to modulate susceptibility to CMS and other high”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The need for additional iron necessitates an increase in intestinal iron uptake and serum iron binding capacity, as well as enhanced mobilization of iron from internal stores.

    “The need for additional iron necessitates an increase in intestinal iron uptake and serum iron binding capacity, as well as enhanced mobilization of iron from internal stores.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Genetic variations in HIF2A, PHD2 and PPARA associate with lower hemoglobins in native Tibetans compared to Han Chinese and with high altitude adaptation in other populations.

    “Genome-wide searches for single-nucleotide polymorphisms (SNP), candidate gene approaches and exome sequencing have identified genetic variations in the HIF2A, PHD2 and PPARA genes that associate with lower hemoglobins in native Tibetans compared to Han Chinese and with high altitude adaptation in other populations.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [173] Yi X Liang Y Huerta-Sanchez E Sequencing of 50 human exomes reveals adaptation to high altitude Science 2010 329 75 8 20595611 PMC3711608 source

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    • cites [174] Xu S Li S Yang Y A genome-wide search for signals of high-altitude adaptation in Tibetans Mol Biol Evol 2010 28 1003 11 20961960 source

      Not checked in the free run.

    • cites [175] Beall CM Cavalleri GL Deng L Natural selection on EPAS1 (HIF2alpha) associated with low hemoglobin concentration in Tibetan highlanders Proc Natl Acad Sci U S A 2010 107 11459 64 20534544 PMC2895075 source

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    • cites [176] Simonson TS Yang Y Huff CD Genetic evidence for high-altitude adaptation in Tibet Science 2010 329 72 5 20466884 source

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    • cites [177] Peng Y Yang Z Zhang H Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas Mol Biol Evol 2010 28 1075 81 21030426 source

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    • cites [178] Aggarwal S Negi S Jha P EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda Proc Natl Acad Sci U S A 2010 107 18961 6 20956315 PMC2973881 source

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    • cites [179] Bigham A Bauchet M Pinto D Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data PLoS Genet 2010 6 PMC2936536 20838600 source

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    • cites [180] van Patot MC Gassmann M Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2alpha High Alt Med Biol 2011 12 157 67 21718164 source

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  • May combine two claims.

    Premisecitation

    Native Tibetans have higher resting ventilation and hypoxic ventilatory response at comparable altitudes than native Andeans.

    “Native Tibetans have higher resting ventilation and hypoxic ventilatory response at comparable altitudes”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [169] Beall CM Almasy LA Blangero J Percent of oxygen saturation of arterial hemoglobin among Bolivian Aymara at 3,900–4,000 m Am J Phys Anthropol 1999 108 41 51 9915300

      Not checked in the free run.

    • cites [170] Beall CM Tibetan and Andean contrasts in adaptation to high-altitude hypoxia Adv Exp Med Biol 2000 475 63 74 10849649

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  • May combine two claims.

    Interpretationreasoning

    In iron-deficient states and/or under hypoxic conditions, the liver makes less hepcidin and intestinal iron uptake is enhanced.

    “Thus, in iron-deficient states (e.g. iron-deficiency anemia) and/or under hypoxic conditions (e.g. ascent to high altitude) the liver makes less hepcidin and intestinal iron uptake is enhanced”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Tibetan residents of Han Chinese descent are much more frequently affected by CMS than native Tibetans, and this represents a major public health burden.

    “In contrast, Tibetan residents of Han Chinese descent are much more frequently affected by CMS, which represents a major public health burden.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [165] Penaloza D Arias-Stella J The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness Circulation 2007 115 1132 46 17339571 source

      Not checked in the free run.

    • cites [166] Pei SX Chen XJ Si Ren BZ Chronic mountain sickness in Tibet Q J Med 1989 71 555 74 2513594 source

      Not checked in the free run.

    • cites [167] Moore LG Niermeyer S Zamudio S Human adaptation to high altitude: regional and life-cycle perspectives Am J Phys Anthropol 1998 Suppl 27 25 64 9881522 source

      Not checked in the free run.

    • cites [168] Pei T Li X Tao F Burden of disease resulting from chronic mountain sickness among young Chinese male immigrants in Tibet BMC Public Health 2012 12 401 22672510 PMC3444415 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated hepcidin leads to reduced ferroportin surface expression and hypoferremia.

    “and lead to reduced ferroportin surface expression and hypoferremia”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [188] Ganz T Molecular control of iron transport J Am Soc Nephrol 2007 18 394 400 17229910 source

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    • cites [189] Ganz T Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation Blood 2003 102 783 8 12663437 source

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  • May combine two claims.

    Premisecitation

    There is less intrauterine growth retardation and better neonatal oxygenation among native Tibetans compared to native Andeans or Han Chinese.

    “There is also less intrauterine growth retardation and better neonatal oxygenation among native Tibetans compared to native Andeans or Han Chinese.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [167] Moore LG Niermeyer S Zamudio S Human adaptation to high altitude: regional and life-cycle perspectives Am J Phys Anthropol 1998 Suppl 27 25 64 9881522

      Not checked in the free run.

    • cites [171] Moore LG Armaza F Villena M Vargas E Comparative aspects of high-altitude adaptation in human populations Adv Exp Med Biol 2000 475 45 62 10849648

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    CMS prevalence is higher in men than in women, increases with altitude and age, and is more likely in the presence of lung diseases, smoking and environmental pollution.

    “Prevalence of CMS is higher in men than in women, increases with altitude and age, and is more likely to develop in the presence of lung diseases, smoking and environmental pollution.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Penaloza D Arias-Stella J The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness Circulation 2007 115 1132 46 17339571

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TMPRSS6 is HIF-regulated and is predicted to blunt BMP6/HJV-mediated signals under hypoxic conditions.

    “Similarly, transmembrane protease serine 6 (TMPRSS6), also known as matriptase-2, was reported to be HIF-regulated and is predicted to blunt BMP6/HJV-mediated signals under hypoxic conditions.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [205] Du X She E Gelbart T The serine protease TMPRSS6 is required to sense iron deficiency Science 2008 320 1088 92 18451267 PMC2430097

      Not checked in the free run.

    • cites [206] Lakhal S Schodel J Townsend AR Pugh CW Ratcliffe PJ Mole DR Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis J Biol Chem 2010 286 4090 7 20966077 PMC3039360

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    • cites [207] Silvestri L Pagani A Nai A De Domenico I Kaplan J Camaschella C The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin Cell Metab 2008 8 502 11 18976966 PMC2648389

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  • May combine two claims.

    Premisecitation

    Serum iron and ferritin levels are decreased in Chuvash patients and in individuals sojourning at high altitude for 10-12 days.

    “Serum iron and ferritin levels are decreased in Chuvash patients and in individuals sojourning at high altitude for 10–12 days.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [191] Gordeuk VR Miasnikova GY Sergueeva AI Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression Blood 2011 118 5278 82 21876117 PMC3217409 source

      Not checked in the free run.

    • cites [211] Piperno A Galimberti S Mariani R Modulation of hepcidin production during hypoxia-induced erythropoiesis in humans in vivo: data from the HIGHCARE project Blood 2011 117 2953 9 21149632 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF induces furin, which cleaves HJV and generates a soluble form of HJV, which suppresses hepcidin by antagonizing BMP6 signaling.

    “Recent in vivo studies have shown that HIF induces furin, a proprotein convertase that cleaves HJV and generates a soluble form of HJV, which suppresses hepcidin by antagonizing BMP6 signaling.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [203] Silvestri L Pagani A Camaschella C Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis Blood 2008 111 924 31 17938254 source

      Not checked in the free run.

    • cites [204] McMahon S Grondin F McDonald PP Richard DE Dubois CM Hypoxia-enhanced expression of the proprotein convertase furin is mediated by hypoxia-inducible factor-1: impact on the bioactivation of proproteins J Biol Chem 2005 280 6561 9 15611046 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Previous reports found that higher doses of GDF15 were needed to achieve hepcidin suppression in human HuH-7 hepatoma cells and primary hepatocytes, while low dose GDF15 treatment increased hepcidin.

    “This is in contrast to previous reports where higher doses of GDF15 were needed to achieve hepcidin suppression in human HuH-7 hepatoma cells and in primary hepatocytes, while low dose GDF15 treatment increased hepcidin.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [214] Tanno T Bhanu NV Oneal PA High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin Nat Med 2007 13 1096 101 17721544 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GDF15 is an iron- and O2-regulated (HIF-independent) member of the TGF-β superfamily, secreted from maturing erythroblasts, and has been shown to suppress hepcidin transcription in primary human hepatocytes and hepatoma cells.

    “GDF15 is an iron- and O2-regulated (HIF-independent) member of the TGF-β superfamily, which is secreted from maturing erythroblasts and has been shown to suppress hepcidin transcription in primary human hepatocytes and hepatoma cells”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [214] Tanno T Bhanu NV Oneal PA High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin Nat Med 2007 13 1096 101 17721544 source

      Not checked in the free run.

    • cites [217] Lakhal S Talbot NP Crosby A Regulation of growth differentiation factor 15 expression by intracellular iron Blood 2009 113 1555 63 19047680 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    HIF-2 is a direct regulator of both renal and hepatic EPO synthesis, but regulates hepcidin only indirectly via stimulation of bone marrow activity.

    “HIF-2 is a direct regulator of both renal and hepatic EPO synthesis, but regulates hepcidin only indirectly via stimulation of bone marrow activity”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [197] Volke M Gale DP Maegdefrau U Evidence for a lack of a direct transcriptional suppression of the iron regulatory peptide hepcidin by hypoxia-inducible factors PLoS ONE 2009 4 e7875 19924283 PMC2773926

      Not checked in the free run.

    • cites [208] Liu Q Davidoff O Niss K Haase VH Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis J Clin Invest 2012 122 4635 44 23114598 PMC3533545

      Not checked in the free run.

    • cites [210] Mastrogiannaki M Matak P Mathieu JR Hepatic HIF-2 down-regulates hepcidin expression in mice through epo-mediated increase in erythropoiesis Haematologica 2012 97 824 34 PMC3366646 22207682

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The acute decrease of serum hepcidin at high altitude precedes changes in serum ferritin and transferrin saturation, suggesting that under hypoxic conditions hepcidin regulation is, at least initially, iron-independent.

    “Time course analysis, however, indicated that the acute decrease of serum hepcidin at high altitude preceded changes in serum ferritin and transferrin saturation, suggesting that under hypoxic conditions hepcidin regulation is, at least initially, iron-independent.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [212] Talbot NP Lakhal S Smith TG Regulation of hepcidin expression at high altitude Blood 2012 119 857 60 22130801

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Experimental studies in cultured cells, animal models and human subjects have established that hepcidin production is O2-sensitive and involves the HIF pathway.

    “Experimental studies in cultured cells, in animal models and in human subjects have established that hepcidin production is O2-sensitive and involves the HIF pathway.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [126] Ang SO Chen H Hirota K Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia Nature Genetics 2002 32 614 21 12415268 source

      Not checked in the free run.

    • cites [191] Gordeuk VR Miasnikova GY Sergueeva AI Chuvash polycythemia VHLR200W mutation is associated with down-regulation of hepcidin expression Blood 2011 118 5278 82 21876117 PMC3217409 source

      Not checked in the free run.

    • cites [192] Nicolas G Chauvet C Viatte L The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation J Clin Invest 2002 110 1037 44 12370282 PMC151151 source

      Not checked in the free run.

    • cites [193] Peyssonnaux C Zinkernagel AS Schuepbach RA Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs) J Clin Invest 2007 117 1926 32 17557118 PMC1884690 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    HIF-2 induces EPO production in kidney and liver (depending on the severity of hypoxia), resulting in increased serum EPO levels and stimulation of erythropoiesis, which subsequently leads to suppression of hepcidin in the liver.

    “HIF-2 induces EPO production in kidney and in liver (depending on the severity of hypoxia), resulting in increased serum EPO levels and stimulation of erythropoiesis, which subsequently leads to the suppression of hepcidin in the liver.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Haase VH Hypoxic regulation of erythropoiesis and iron metabolism Am J Physiol Renal Physiol 2010 299 F1 13 20444740 PMC2904169

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    VCAM-1 is an integrin receptor that binds VLA4 on erythroblasts and supports erythroid maturation.

    “an integrin receptor that binds very late antigen-4 (VLA4) on erythroblasts and supports erythroid maturation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mice with globally reduced HIF-2 expression displayed a defect in erythroid maturation, which was dependent on the expression levels of VCAM-1.

    “as mice with globally reduced HIF-2 expression displayed a defect in erythroid maturation, which was dependent on the expression levels of vascular adhesion molecule (VCAM)-1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Yamashita T Ohneda O Sakiyama A Iwata F Ohneda K Fujii-Kuriyama Y The microenvironment for erythropoiesis is regulated by HIF-2alpha through VCAM-1 in endothelial cells Blood 2008 112 1482 92 18451309

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inducible, global deletion of PHD2 in adult mice resulted in severe erythrocytosis from a dramatic increase in renal EPO production (Hct values > 80%), as well as other organ pathologies, particularly when PHD3 was inactivated simultaneously.

    “Inducible, global deletion of PHD2 in adult mice resulted in severe erythrocytosis from a dramatic increase in renal EPO production (Hct values > 80%), as well as other organ pathologies, in particular when PHD3 was inactivated simultaneously.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [237] Takeda K Cowan A Fong GH Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system Circulation 2007 116 774 81 17646578 source

      Not checked in the free run.

    • cites [238] Takeda K Ho VC Takeda H Duan LJ Nagy A Fong GH Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2 Mol Cell Biol 2006 26 8336 46 16966370 PMC1636770 source

      Not checked in the free run.

    • cites [239] Minamishima YA Moslehi J Bardeesy N Cullen D Bronson RT Kaelin WG Jr Somatic inactivation of the PHD2 prolyl hydroxylase causes polycythemia and congestive heart failure Blood 2008 111 3236 44 18096761 PMC2265460 source

      Not checked in the free run.

    • cites [240] Takeda K Aguila HL Parikh NS Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins Blood 2008 111 3229 35 18056838 PMC2265459 source

      Not checked in the free run.

    • cites [241] Minamishima YA Moslehi J Padera RF Bronson RT Liao R Kaelin WG Jr A feedback loop involving the Phd3 prolyl hydroxylase tunes the mammalian hypoxic response in vivo Molecular and Cellular Biology 2009 29 5729 41 19720742 PMC2772748 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PHD1- and PHD3-deficient mice developed mild to moderate erythrocytosis (Hct of 67% compared to 53% in control mice) only when both enzymes were inactivated simultaneously, with the liver being the source of EPO and not the kidney.

    “PHD1- and PHD3-deficient mice, which in contrast to conventional PHD2 knockout mice survive into adulthood, developed mild to moderate erythrocytosis (Hct of 67% compared to 53% in control mice) only when both enzymes were inactivated simultaneously, the liver being the source of EPO and not the kidney.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Minamishima YA Kaelin WG Jr Reactivation of hepatic EPO synthesis in mice after PHD loss Science 2010 329 407 20651146 PMC3668543

      Not checked in the free run.

    • cites [240] Takeda K Aguila HL Parikh NS Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins Blood 2008 111 3229 35 18056838 PMC2265459

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia stimulates EPOR expression and regulates components of the hemoglobin synthesis pathway.

    “Hypoxia stimulates EPOR expression and regulates components of the hemoglobin synthesis pathway.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [52] Chin K Yu X Beleslin-Cokic B Production and processing of erythropoietin receptor transcripts in brain Brain Res Mol Brain Res 2000 81 29 42 11000476

      Not checked in the free run.

    • cites [53] Manalo DJ Rowan A Lavoie T Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1 Blood 2005 105 659 69 15374877 source

      Not checked in the free run.

    • cites [54] Yoon D Pastore YD Divoky V HIF-1alpha -deficiency results in dysregulated EPO signaling and iron homeostasis in mouse development J Biol Chem 2006 281 25703 11 16787915

      Not checked in the free run.

    • cites [226] Liu YL Ang SO Weigent DA Prchal JT Bloomer JR Regulation of ferrochelatase gene expression by hypoxia Life Sci 2004 75 2035 43 15312748

      Not checked in the free run.

    • cites [227] Hofer T Wenger RH Kramer MF Ferreira GC Gassmann M Hypoxic up-regulation of erythroid 5-aminolevulinate synthase Blood 2003 101 348 50 12393745

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased serum GDF15 levels were found following DFO treatment, suggesting iron-dependent regulation.

    “Similarly, increased serum GDF15 levels were found following DFO treatment, suggesting iron-dependent regulation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Lakhal S Talbot NP Crosby A Regulation of growth differentiation factor 15 expression by intracellular iron Blood 2009 113 1555 63 19047680

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Therapy with recombinant EPO eliminates the need for rbc transfusions, improves cardiovascular function and cognitive ability.

    “Therapy with recombinant EPO eliminates the need for rbc transfusions, improves cardiovascular function and cognitive ability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the oncology setting, high dose recombinant EPO administration was associated with tumor growth and increased overall mortality.

    “Furthermore, in the Oncology setting high dose recombinant EPO administration was found to be associated with tumor growth and increased overall mortality”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [232] Besarab A Frinak S Yee J What is so bad about a hemoglobin level of 12 to 13 g/dL for chronic kidney disease patients anyway? Adv Chronic Kidney Dis 2009 16 131 42 19233072

      Not checked in the free run.

    • cites [233] Spivak JL Gascon P Ludwig H Anemia management in oncology and hematology The Oncologist 2009 14 Suppl 1 43 56 19762516

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Intermittent HIF activation over prolonged periods may lead to changes in glucose, fat and cholesterol metabolism, promote angiogenesis and have other adverse effects.

    “intermittent HIF activation over prolonged periods of time may lead to changes in glucose, fat and cholesterol metabolism, promote angiogenesis and have other adverse effects.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [245] Semenza GL HIF-1: upstream and downstream of cancer metabolism Current Opinion in Genetics and Development 2009 20 51 6 19942427 PMC2822127

      Not checked in the free run.

    • cites [246] Cantley J Selman C Shukla D Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice J Clin Invest 2009 119 125 35 19065050 PMC2613475

      Not checked in the free run.

    • cites [247] Cheng K Ho K Stokes R Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets J Clin Invest 2010 120 2171 83 20440072 PMC2877560 source

      Not checked in the free run.

    • cites [248] Rankin EB Rha J Selak MA Hypoxia-inducible factor 2 regulates hepatic lipid metabolism Mol Cell Biol 2009 29 4527 38 19528226 PMC2725738

      Not checked in the free run.

    • cites [249] Zehetner J Danzer C Collins S PVHL is a regulator of glucose metabolism and insulin secretion in pancreatic beta cells Genes Dev 2008 22 3135 46 19056893 PMC2593613

      Not checked in the free run.

    • cites [250] Krishnan J Suter M Windak R Activation of a HIF1alpha-PPARgamma axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy Cell Metabolism 2009 9 512 24 19490906

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    HIF-2 acts as a central regulator of hypoxia-induced erythropoiesis, coordinating EPO synthesis with iron metabolism and erythroid progenitor maturation.

    “This finding lends more support to the concept that HIF-2 acts a central regulator of hypoxia-induced erythropoiesis, which coordinates EPO synthesis with iron metabolism and erythroid progenitor maturation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Liver-specific PHD inhibition using siRNA has been shown to correct Hgb values in preclinical models of renal anemia and anemia of chronic inflammation, associated with decreased hepcidin expression in the liver.

    “Liver-specific PHD inhibition using siRNA has been shown to correct Hbg values in preclinical models of renal anemia and anemia of chronic inflammation, which was associated with decreased hepcidin expression in the liver.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Querbes W Bogorad RL Moslehi J Treatment of erythropoietin deficiency in mice with systemically administered siRNA Blood 2012 120 1916 22 22611156 PMC3433093

      Not checked in the free run.

45 of 45

Claims other papers make about this one

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Cites

1 retracted

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Research works printed but not linked: 1

  1. Viault, 1890, Sur laugmentation considérable du nombre des globules rouges dans le sang chez les inhabitants des hauts plateaux de l'Amérique du Sud, C R Acad Sci Paris, 111, 917

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Authors
Haase, V. H.
Affiliations
Vanderbilt University (US)
Corresponding author
Haase, Volker H.
ORCID
Haase, Volker H.
Venue
Blood Reviews
Publisher
Elsevier BV
Published
2013-01
Volume
27
Issue
1
Pages
41-53
ISSN
0268-960X (ISSN-L)
DOI
10.1016/j.blre.2012.12.003
PMC
PMC3731139
OpenAlex
W2106855201
Semantic Scholar
15221fc3cd3b20af14db6c9b0c7fc03a8be2a312
Cited by
787
References
258
Citations by year
2026: 66 · 2025: 90 · 2024: 89 · 2023: 63 · 2022: 65 · 2021: 72 · 2020: 80 · 2019: 50 · 2018: 56 · 2017: 38 · 2016: 39 · 2015: 33 · 2014: 34 · 2013: 11
FWCI
5.95
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Blood Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Krick-Brooks chair in Nephrology
  • National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK)
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
erythropoiesis, hypoxia-inducible factor, erythropoietin, HIF-2, iron metabolism, intestinal iron absorption, bone marrow microenvironment, high-altitude adaptation, familial erythrocytosis, anemia treatment
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Hypoxia, Bone Marrow Cells, Cell Differentiation, Erythrocytes, Erythropoiesis, Erythropoietin, Gene Expression Regulation, Humans, Iron, Kidney, Liver, Oxygen, Signal Transduction, Cell Proliferation, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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