Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients

BackgroundIron is essential not only for erythropoisis but also for several bioenergetics’ processes in myocardium. Hepcidin is a well-known regulator of iron homeostasis. Recently, researchers identified low hepcidin was independently associated with increased 3-year mortality among systolic heart failure patients. In addition, our previous in vivo study revealed that the left ventricular mass index increased in chronic kidney disease patients with lower serum hepcidin. We hypothesize that hepcidin interacts with the apoptotic pathway of cardiomyocytes during oxidative stress conditions.MethodsTo test this hypothesis, human cardiomyocytes were cultured and treated with ferrous iron. The possible underlying signaling pathways of cardiotoxicity were examined following knockdown studies using siRNAs of hepcidin (siRNA1 was used as a negative control and siRNA2 was used to silence hepcidin).ResultsWe found that ferrous iron induces apoptosis in human cardiomyocytes in a dose-dependent manner. This iron-induced apoptosis was linked to enhanced caspase 8, reduced Bcl-2, Bcl-xL, phosphorylated Akt and GATA-4. Hepcidin levels increased in human cardiomyocytes pretreated with ferrous iron and returned to non-iron treated levels following siRNA2 transfection. In iron pretreated cardiomyocytes, the siRNA2 transfection further increased caspase 8 expression and decreased the expression of GATA-4, Bcl-2, Bcl-xL and phosphorylated Akt than iron pretreatment alone, but caspase 9 levels remained unchanged.ConclusionsOur findings suggest that hepcidin can rescue human cardiomyocytes from iron-induced apoptosis through the regulation of GATA-4/Bcl-2 and the extrinsic apoptotic pathway.

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“…These results complement our earlier clinical findings that serum hepcidin is significantly negatively correlated with LVM and LVMI [26]. …”

Section: Discussionsupporting

confidence: 91%

Silencing of hepcidin enforces the apoptosis in iron-induced human cardiomyocytes

Hsieh

Huang

Lee

et al. 2014

J Occup Med Toxicol

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“…In dialysis children and adolescents with iron overload, ferritin levels showed a positive correlation with CRP, IL-6 and LVM [ 39 ]. On the other hand, decreased levels of serum hepcidin were associated with a higher LVM index in ND-CKD patients [ 172 ]. However, serum hepcidin levels were increased and positively correlated with brachial-ankle pulse wave velocity as the measurement of arterial stiffness in HD adults [ 173 ].…”

Section: Role Of Ferritin Hepcidin and Inflammation For The Develmentioning

confidence: 99%

Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease

2018

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Iron deficiency anemia (IDA) is a major problem in chronic kidney disease (CKD), causing increased mortality. Ferritin stores iron, representing iron status. Hepcidin binds to ferroportin, thereby inhibiting iron absorption/efflux. Inflammation in CKD increases ferritin and hepcidin independent of iron status, which reduce iron availability. While intravenous iron therapy (IIT) is superior to oral iron therapy (OIT) in CKD patients with inflammation, OIT is as effective as IIT in those without. Inflammation reduces predictive values of ferritin and hepcidin for iron status and responsiveness to iron therapy. Upper limit of ferritin to predict iron overload is higher in CKD patients with inflammation than in those without. However, magnetic resonance imaging studies show lower cutoff levels of serum ferritin to predict iron overload in dialysis patients with apparent inflammation than upper limit of ferritin proposed by international guidelines. Compared to CKD patients with inflammation, optimal ferritin levels for IDA are lower in those without, requiring reduced iron dose and leading to decreased mortality. The management of IDA should differ between CKD patients with and without inflammation and include minimization of inflammation. Further studies are needed to determine the impact of inflammation on ferritin, hepcidin and therapeutic strategy for IDA in CKD.

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“…87 However, even in these patients, iron deficiency lowers liver hepcidin expression, confirming the crucial role of iron status in hepcidin regulation. 88 Systemic hepcidin levels can serve as a therapeutic target in CKD because according to the study from Hsieh et al, low levels of serum hepcidin in CKD are negative predictors of left ventricular hypertrophy. 88 Still,…”

Section: Role Of Systemic Hepcidin In Heart Homeostasismentioning

confidence: 99%

“…88 Systemic hepcidin levels can serve as a therapeutic target in CKD because according to the study from Hsieh et al, low levels of serum hepcidin in CKD are negative predictors of left ventricular hypertrophy. 88 Still,…”

Section: Role Of Systemic Hepcidin In Heart Homeostasismentioning

confidence: 99%

Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology

Vela

2018

Laboratory Investigation

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Hepcidin is the main regulator of iron metabolism in tissues. Its serum levels are mostly correlated with the levels of hepcidin expression from the liver, but local hepcidin can be important for the physiology of other organs as well. There is an increasing evidence that this is the case with cardiac hepcidin. This has been confirmed by studies with models of ischemic heart disease and other heart pathologies. In this review the discussion dissects the role of cardiac hepcidin in cellular homeostasis. This review is complemented with examination of the role of systemic hepcidin in heart disease and its use as a biochemical marker. The relationship between systemic vs local hepcidin in the heart is important because it can help us understand how the fine balance between the actions of two hepcidins affects heart function. Manipulating the axis systemic/cardiac hepcidin could serve as a new therapeutic strategy in heart diseases.

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Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients

Cited by 9 publications

References 21 publications

Silencing of hepcidin enforces the apoptosis in iron-induced human cardiomyocytes

Silencing of hepcidin enforces the apoptosis in iron-induced human cardiomyocytes

Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease

Balance of cardiac and systemic hepcidin and its role in heart physiology and pathology

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