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Cardiac Hepcidin Expression Associates with Injury Independent of Iron
G Fenna van Breda1, Lennart G Bongartz, Wenqing Zhuang
1Department of Nephrology and Immunology, University of Alberta, Edmonton, Alta., Canada.
Insights
Cardiac hepcidin gene expression increases with heart injury and kidney disease, independent of iron levels. Liver hepcidin regulation differs, decreasing with combined kidney and heart issues.
Area of Science:
- Cardiovascular Biology
- Renal Physiology
- Iron Metabolism
Background:
- Hepcidin, a key regulator of iron homeostasis, is primarily produced in the liver but also in the heart.
- Understanding cardiac hepcidin regulation is crucial, especially in conditions involving cardiac and renal dysfunction.
- Myocardial infarction (MI) and chronic kidney disease (CKD) can impact systemic and local iron regulation.
Purpose of the Study:
- To investigate the differential regulation of hepcidin gene expression in the heart and liver.
- To determine the role of cardiac injury (MI) and remote stimuli (CKD) in modulating cardiac hepcidin.
- To assess the influence of local iron content on cardiac hepcidin expression.
Main Methods:
- A rat model was established with subtotal nephrectomy (SNX) for CKD and coronary ligation (CL) for MI, creating four groups: control, SNX, CL, and SNX + CL.
- Gene expression of hepcidin, iron markers, and damage markers in cardiac and liver tissues was analyzed using quantitative polymerase chain reaction.
- Ferritin protein expression was evaluated by immunohistochemistry in both tissue types.
Main Results:
- Cardiac hepcidin mRNA expression significantly increased following CL (2-fold) and SNX (3-fold).
- Cardiac hepcidin mRNA levels positively correlated with markers of cardiac stress, such as brain natriuretic peptide and connective tissue growth factor.
- Liver hepcidin expression remained unchanged with isolated SNX or CL but decreased by 50% in the combined SNX + CL group. Hepatic and cardiac ferritin levels did not differ significantly across groups.
Conclusions:
- Cardiac hepcidin gene expression is differentially regulated compared to liver hepcidin.
- Cardiac hepcidin induction appears primarily driven by the severity of cardiac injury and associated stress, rather than local iron accumulation.
- These findings highlight a distinct role for cardiac hepcidin in renocardiac failure, influenced by injury stimuli.
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.
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