RGD Reference Report - Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats. - Rat Genome Database

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Hepcidin as a predictive factor and therapeutic target in erythropoiesis-stimulating agent treatment for anemia of chronic disease in rats.

Authors: Theurl, M  Nairz, M  Schroll, A  Sonnweber, T  Asshoff, M  Haschka, D  Seifert, M  Willenbacher, W  Wilflingseder, D  Posch, W  Murphy, AT  Witcher, DR  Theurl, I  Weiss, G 
Citation: Theurl M, etal., Haematologica. 2014 Sep;99(9):1516-24. doi: 10.3324/haematol.2013.099481. Epub 2014 Jun 3.
RGD ID: 11041618
Pubmed: PMID:24895335   (View Abstract at PubMed)
PMCID: PMC4562542   (View Article at PubMed Central)
DOI: DOI:10.3324/haematol.2013.099481   (Journal Full-text)

Anemia of chronic disease is a multifactorial disorder, resulting mainly from inflammation-driven reticuloendothelial iron retention, impaired erythropoiesis, and reduced biological activity of erythropoietin. Erythropoiesis-stimulating agents have been used for the treatment of anemia of chronic disease, although with varying response rates and potential adverse effects. Serum concentrations of hepcidin, a key regulator of iron homeostasis, are increased in patients with anemia of chronic disease and linked to the pathogenesis of this disease, because hepcidin blocks cellular iron egress, thus limiting availability of iron for erythropoiesis. We tested whether serum hepcidin levels can predict and affect the therapeutic efficacy of erythropoiesis-stimulating agent treatment using a well-established rat model of anemia of chronic disease. We found that high pre-treatment hepcidin levels correlated with an impaired hematologic response to an erythropoiesis-stimulating agent in rats with anemia of chronic disease. Combined treatment with an erythropoiesis-stimulating agent and an inhibitor of hepcidin expression, LDN-193189, significantly reduced serum hepcidin levels, mobilized iron from tissue stores, increased serum iron levels and improved hemoglobin levels more effectively than did the erythropoiesis-stimulating agent or LDN-193189 monotherapy. In parallel, both the erythropoiesis-stimulating agent and erythropoiesis-stimulating agent/LDN-193189 combined reduced the expression of cytokines known to inhibit erythropoiesis. We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease. Pharmacological inhibition of hepcidin formation improves the erythropoiesis-stimulating agent's therapeutic efficacy, which may favor a reduction of erythropoiesis-stimulating agent dosages, costs and side effects.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HAMPHumananemia treatmentISOHamp (Rattus norvegicus)associated with InflammationRGD 
HampRatanemia treatmentIDA associated with InflammationRGD 
HampMouseanemia treatmentISOHamp (Rattus norvegicus)associated with InflammationRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Cellular Component

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HampRatextracellular space  IDA  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hamp  (hepcidin antimicrobial peptide)

Genes (Mus musculus)
Hamp  (hepcidin antimicrobial peptide)

Genes (Homo sapiens)
HAMP  (hepcidin antimicrobial peptide)


Additional Information