Abstract
We examined changes in hepcidin (closely associated with anemia of chronic inflammation (ACI)) and upstream regulatory pathways after intravenous (IV) iron supplementation in an ACI animal model. ACI was induced in male Sprague-Dawley rats by intraperitoneally administering complete Freund's adjuvant (CFA). Two weeks after starting CFA treatment, ACI rats received IV iron (CFA-iron) or vehicle (CFA-saline). Three days after IV iron treatment, iron profiles, hepcidin levels, and expression of proteins involved in the signaling pathways upstream of hepcidin transcription in the liver were measured. In CFA-treated rats, anemia with a concomitant increase in the levels of serum inflammatory cytokines and reactive oxygen species occurred. In CFA-iron rats, hemoglobin (Hb) concentration was still lower than that in control rats. In CFA-saline rats, hepatic hepcidin and ferritin levels increased compared with those in control rats and were further increased in CFA-iron rats. In CFA-saline rats, NADPH oxidase- (NOX-) 2, NOX-4, and superoxide dismutase levels in the liver were upregulated compared with those in control rats and their levels were further increased in CFA-iron rats. In CFA-saline rats, activities of the IL-6/STAT and BMP/SMAD pathways were enhanced in the liver compared with those in control rats and their levels were further increased in CFA-iron rats, whereas IL-6 expression remained unaffected after IV iron administration. In HepG2 cells, iron caused phosphorylation of STAT-3 and SMAD1/5 and knockdown of STAT-3 and SMAD1/5 using siRNAs reduced iron-induced hepcidin upregulation to levels similar to those in corresponding control cells. Renal erythropoietin expression and serum erythroferrone concentration were lower in CFA-iron rats than those in control rats. In ACI rats, IV iron supplementation did not recover Hb within three days despite an increase in hepatic ferritin levels, which might be attributable to an additional increase in hepcidin levels that was already upregulated under ACI conditions. Both STAT-3 phosphorylation and SMAD1/5 phosphorylation were associated with hepcidin upregulation after IV iron treatment, and this seems to be linked to iron-induced oxidative stress.
Highlights
Anemia of chronic inflammation (ACI), referred to as anemia of chronic disease, is the second most common type of anemia after iron deficiency anemia (IDA) in hospitalized patients and is associated with increased morbidity [1, 2]
complete Freund’s adjuvant (CFA)-treated rats (ACI rats) gained an average of 88 g, whereas rats in the control group gained an average of 102 g over the course of the two-week experimental period
Hepatic hepcidin protein activity was upregulated in CFAtreated rats, and IV iron supplementation at a clinically relevant dose intensified the degree of hepatic hepcidin upregulation
Summary
Anemia of chronic inflammation (ACI), referred to as anemia of chronic disease, is the second most common type of anemia after iron deficiency anemia (IDA) in hospitalized patients and is associated with increased morbidity [1, 2]. Inadequate utilization of iron despite sufficient body iron stores leads to the development of ACI, whereas IDA is caused by an absolute iron deficiency [3]. Hepcidin is upregulated by an increase in iron stores in the body and inflammatory conditions and is downregulated by erythropoiesis [4, 5]. Iron-mediated regulation of hepcidin levels acts mainly through the bone morphogenetic protein (BMP)/Sma mothers against the decapentaplegic (SMAD) signaling pathway. Iron supplementation and blood transfusion are the only clinical treatment regimens for iron deficiency and anemia, regardless of the underlying mechanisms
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