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In-depth review: is hepcidin a marker for the heart and the kidney?

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Abstract

Iron is an essential trace element involved in oxidation–reduction reactions, oxygen transport and storage, and energy metabolism. Iron in excess can be toxic for cells, since iron produces reactive oxygen species and is important for survival of pathogenic microbes. There is a fine-tuning in the regulation of serum iron levels, determined by intestinal absorption, macrophage iron recycling, and mobilization of hepatocyte stores versus iron utilization, primarily by erythroid cells in the bone marrow. Hepcidin is the major regulatory hormone of systemic iron homeostasis and is upregulated during inflammation. Hepcidin metabolism is altered in chronic kidney disease. Ferroportin is an iron export protein and mediates iron release into the circulation from duodenal enterocytes, splenic reticuloendothelial macrophages, and hepatocytes. Systemic iron homeostasis is controlled by the hepcidin–ferroportin axis at the sites of iron entry into the circulation. Hepcidin binds to ferroportin, induces its internalization and intracellular degradation, and thus inhibits iron absorption from enterocytes, and iron release from macrophages and hepatocytes. Recent data suggest that hepcidin, by slowing or preventing the mobilization of iron from macrophages, may promote atherosclerosis and may be associated with increased cardiovascular disease risk. This article reviews the current data regarding the molecular and cellular pathways of systemic and autocrine hepcidin production and seeks the answer to the question whether changes in hepcidin translate into clinical outcomes of all-cause and cardiovascular mortality, and cardiovascular and renal end-points.

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Fig. 1
Fig. 2
Fig. 3

source of iron deposits within the plaques. CD36 is the major scavenger receptor for Ox-LDL. Expression of CD36 is upregulated by hepcidin and Ox-LDL. Cholesterol efflux in macrophages is by cholesterol transporters ATP-binding cassette subfamily A1 (ABCA1) and subfamily G1 (ABCG1). Ox-LDL uptake by macrophages results in induction of CD36 and peroxisome proliferator-activated receptor gamma (PPARγ), which then activates liver receptor X (LXR) to upregulate ABCA1 and ABCG1 gene expression, subsequently stimulating cellular cholesterol efflux mediated by apolipoprotein A-I (ApoA-I) and high-density lipoprotein (HDL), respectively. There is a vicious cycle between TLR-4/ NF-κB activation and autocrine formation of hepcidin-induced iron retention. Hepcidin suppresses Ox-LDL-induced upregulation of proteins involved in macrophage cholesterol efflux

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Authors and Affiliations

  1. Department of Nephrology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey

    Rengin Elsurer Afsar

  2. Department of Nephrology, Faculty of Medicine, Koc University, Istanbul, Turkey

    Mehmet Kanbay

  3. Department of Nephrology, Afyon Kocatepe Devlet Hastanesi, Afyon, Turkey

    Avsin Ibis

  4. Department of Nephrology, Faculty of Medicine, Suleyman Demirel University, Isparta, Turkey

    Baris Afsar

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REA is the co-owner of the project, wrote the manuscript, and approved the version to be published. MK reviewed the literature, helped in writing the manuscript, and approved the version to be published. AI helped in writing the manuscript and approved the version to be published. BA is the co-owner of the project, revised it critically for important intellectual content, and approved the version to be published.

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Correspondence to Rengin Elsurer Afsar.

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Afsar, R.E., Kanbay, M., Ibis, A. et al. In-depth review: is hepcidin a marker for the heart and the kidney?. Mol Cell Biochem 476, 3365–3381 (2021). https://doi.org/10.1007/s11010-021-04168-4

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