Cardiac Hepcidin Expression Associates with Injury Independent of Iron

Am J Nephrol. 2016;44(5):368-378. doi: 10.1159/000449419. Epub 2016 Oct 22.


Background: Hepcidin regulates systemic iron homeostasis by downregulating the iron exporter ferroportin. Circulating hepcidin is mainly derived from the liver but hepcidin is also produced in the heart. We studied the differential and local regulation of hepcidin gene expression in response to myocardial infarction (MI) and/or chronic kidney disease (CKD). We hypothesized that cardiac hepcidin gene expression is induced by and regulated to severity of cardiac injury, either through direct (MI) or remote (CKD) stimuli, as well as through increased local iron content.

Methods: Nine weeks after subtotal nephrectomy (SNX) or sham surgery (CON), rats were subjected to coronary ligation (CL) or sham surgery to realize 4 groups: CON, SNX, CL and SNX + CL. In week 16, the gene expression of hepcidin, iron and damage markers in cardiac and liver tissues was assessed by quantitative polymerase chain reaction and ferritin protein expression was studied by immunohistochemistry.

Results: Cardiac hepcidin messenger RNA (mRNA) expression was increased 2-fold in CL (p = 0.03) and 3-fold in SNX (p = 0.01). Cardiac ferritin staining was not different among groups. Cardiac hepcidin mRNA expression correlated with mRNA expression levels of brain natriuretic peptide (β = 0.734, p < 0.001) and connective tissue growth factor (β = 0.431, p = 0.02). In contrast, liver hepcidin expression was unaffected by SNX and CL alone, while it had decreased 50% in SNX + CL (p < 0.05). Hepatic ferritin immunostaining was not different among groups.

Conclusions: Our data indicate differences in hepcidin regulation in liver and heart and suggest a role for injury rather than iron as the driving force for cardiac hepcidin expression in renocardiac failure.

MeSH terms

  • Animals
  • Bone Morphogenetic Protein 6 / metabolism
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cation Transport Proteins / metabolism
  • Connective Tissue Growth Factor / metabolism
  • Cytokines / metabolism
  • Gene Expression Regulation
  • Heme Oxygenase (Decyclizing) / metabolism
  • Hepcidins / metabolism*
  • Iron / metabolism*
  • Liver / metabolism*
  • Male
  • Myocardial Infarction / metabolism*
  • Myocardium / metabolism*
  • Natriuretic Peptide, Brain / metabolism
  • Rats, Inbred Lew
  • Renal Insufficiency, Chronic / metabolism*


  • Bmp6 protein, rat
  • Bone Morphogenetic Protein 6
  • CCAAT-Enhancer-Binding Protein-alpha
  • CCN2 protein, rat
  • Cation Transport Proteins
  • Cytokines
  • Hepcidins
  • metal transporting protein 1
  • Natriuretic Peptide, Brain
  • Connective Tissue Growth Factor
  • Iron
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat