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Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice

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Abstract

Purpose

Angiotensin II (ANG II) has been shown to affect iron metabolism through alteration of iron transporters, leading to increased cellular and tissue iron contents. Serum ferritin, a marker of body iron storage, is elevated in various cardiovascular diseases, including hypertension. However, the associated changes in iron absorption and the mechanism underlying increased iron content in a hypertensive state remain unclear.

Methods

The C57BL6/J mice were treated with ANG II to generate a model of hypertension. Mice were divided into three groups: (1) control, (2) ANG II-treated, and (3) ANG II-treated and ANG II receptor blocker (ARB)-administered (ANG II–ARB) groups.

Results

Mice treated with ANG II showed increased serum ferritin levels compared to vehicle-treated control mice. In ANG II-treated mice, duodenal divalent metal transporter-1 and ferroportin (FPN) expression levels were increased and hepatic hepcidin mRNA expression and serum hepcidin concentration were reduced. The mRNA expression of bone morphogenetic protein 6 and CCAAT/enhancer-binding protein alpha, which are regulators of hepcidin, was also down-regulated in the livers of ANG II-treated mice. In terms of tissue iron content, macrophage iron content and renal iron content were increased by ANG II treatment, and these increases were associated with reduced expression of transferrin receptor 1 and FPN and increased expression of ferritin. These changes induced by ANG II treatment were ameliorated by the administration of an ARB.

Conclusions

Angiotensin II (ANG II) altered the expression of duodenal iron transporters and reduced hepcidin levels, contributing to the alteration of body iron distribution.

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Acknowledgments

This work was supported by a JSPS KAKENHI Grant (No. 25750044 to S.T.) and in part by the Regional Innovation Cluster Program and the Setsuro Fujii Memorial Osaka Foundation for Promotion of Fundamental Medical Research (to T.T.), and by a JSPS KAKENHI Grant (No. 24591203 to Y.I.).

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan

    Soichiro Tajima, Yasumasa Ikeda, Hideaki Enomoto, Mizuki Imao, Yuya Horinouchi, Yuki Izawa-Ishizawa, Yoshitaka Kihira & Toshiaki Tamaki

  2. Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan

    Soichiro Tajima

  3. Student Lab, The University of Tokushima Faculty of Medicine, Tokushima, Japan

    Hideaki Enomoto

  4. Department of Medical Pharmacology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    Mizuki Imao, Licht Miyamoto, Keisuke Ishizawa & Koichiro Tsuchiya

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  1. Soichiro Tajima
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  2. Yasumasa Ikeda
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  3. Hideaki Enomoto
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  6. Yuki Izawa-Ishizawa
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Correspondence to Yasumasa Ikeda.

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Tajima, S., Ikeda, Y., Enomoto, H. et al. Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice. Eur J Nutr 54, 709–719 (2015). https://doi.org/10.1007/s00394-014-0749-1

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  • DOI: https://doi.org/10.1007/s00394-014-0749-1

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