RGD Reference Report - Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo. - Rat Genome Database

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Pathways for the regulation of hepcidin expression in anemia of chronic disease and iron deficiency anemia in vivo.

Authors: Theurl, I  Schroll, A  Nairz, M  Seifert, M  Theurl, M  Sonnweber, T  Kulaksiz, H  Weiss, G 
Citation: Theurl I, etal., Haematologica. 2011 Dec;96(12):1761-9. doi: 10.3324/haematol.2011.048926. Epub 2011 Aug 22.
RGD ID: 7242407
Pubmed: PMID:21859731   (View Abstract at PubMed)
PMCID: PMC3232257   (View Article at PubMed Central)
DOI: DOI:10.3324/haematol.2011.048926   (Journal Full-text)

BACKGROUND: Increased levels of hepcidin, the master regulator of iron homeostasis, contribute to the diversion of iron underlying the anemia of chronic disease. Yet hepcidin levels are low in anemia of chronic disease with concomitant true iron deficiency. Here we clarify the different underlying pathways regulating hepcidin expression under these conditions in vivo. DESIGN AND METHODS: We used rat models of iron deficiency anemia, anemia of chronic disease and anemia of chronic disease with concomitant true iron deficiency and investigated upstream signaling pathways controlling hepcidin transcription in the liver. Protein and mRNA levels of iron metabolism genes and genes involved in SMAD1/5/8 and STAT3 signaling were determined by RT-PCR, Western blotting and immunohistochemistry. RESULTS: SMAD1/5/8 phosphorylation and in parallel hepcidin mRNA expression were increased in anemia of chronic disease but significantly down-regulated in anemia of chronic disease with concomitant iron deficiency, either on the basis of phlebotomy or dietary iron restriction. Iron deficiency resulted in reduced bone morphogenetic protein-6 expression and impaired SMAD1/5/8 phosphorylation and trafficking, two key events for hepcidin transcription. Reduced SMAD1/5/8 activity in association with phlebotomy was paralleled by increased expression of the inhibitory factor, SMAD7, dietary iron restriction appeared to impair hepcidin transactivating SMAD pathways via reduction of membrane bound hemojuvelin expression. CONCLUSIONS: This study evaluated hepcidin signaling pathways in anemia of chronic disease with/without concomitant iron deficiency in vivo. While iron deficiency in general decreased bone morphogenetic protein-6 expression, phlebotomy or dietary iron restriction inhibited inflammation driven SMAD1/5/8 mediated hepcidin formation by different pathways, indicating alternate hierarchic signaling networks as a function of the mode and kinetics of iron deficiency. Nonetheless, iron deficiency inducible regulatory pathways can reverse inflammation mediated stimulation of hepcidin expression.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BMP6Humananemia  ISOBmp6 (Rattus norvegicus)mRNA and protein:decreased expression:liverRGD 
Bmp6Ratanemia  IEP mRNA and protein:decreased expression:liverRGD 
Bmp6Mouseanemia  ISOBmp6 (Rattus norvegicus)mRNA and protein:decreased expression:liverRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Bmp6Ratresponse to iron ion  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Bmp6  (bone morphogenetic protein 6)

Genes (Mus musculus)
Bmp6  (bone morphogenetic protein 6)

Genes (Homo sapiens)
BMP6  (bone morphogenetic protein 6)


Additional Information