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Changes in Hepcidin Levels in an Animal Model of Anemia of Chronic Inflammation: Mechanistic Insights Related to Iron Supplementation and Hepcidin Regulation

Authors
 Hye-Bin Kim  ;  Ji Hae Jun  ;  Jae-Kwang Shim  ;  Ju Eun Oh  ;  Cheolhun Lee  ;  Young-Lan Kwak 
Citation
 OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, Vol.2021 : 4357756, 2021-11 
Journal Title
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
ISSN
 1942-0900 
Issue Date
2021-11
Abstract
We examined changes in hepcidin (closely associated with anemia of chronic inflammation (ACI)) and upstream regulatory pathways after intravenous (IV) iron supplementation in an ACI animal model. ACI was induced in male Sprague-Dawley rats by intraperitoneally administering complete Freund's adjuvant (CFA). Two weeks after starting CFA treatment, ACI rats received IV iron (CFA-iron) or vehicle (CFA-saline). Three days after IV iron treatment, iron profiles, hepcidin levels, and expression of proteins involved in the signaling pathways upstream of hepcidin transcription in the liver were measured. In CFA-treated rats, anemia with a concomitant increase in the levels of serum inflammatory cytokines and reactive oxygen species occurred. In CFA-iron rats, hemoglobin (Hb) concentration was still lower than that in control rats. In CFA-saline rats, hepatic hepcidin and ferritin levels increased compared with those in control rats and were further increased in CFA-iron rats. In CFA-saline rats, NADPH oxidase- (NOX-) 2, NOX-4, and superoxide dismutase levels in the liver were upregulated compared with those in control rats and their levels were further increased in CFA-iron rats. In CFA-saline rats, activities of the IL-6/STAT and BMP/SMAD pathways were enhanced in the liver compared with those in control rats and their levels were further increased in CFA-iron rats, whereas IL-6 expression remained unaffected after IV iron administration. In HepG2 cells, iron caused phosphorylation of STAT-3 and SMAD1/5 and knockdown of STAT-3 and SMAD1/5 using siRNAs reduced iron-induced hepcidin upregulation to levels similar to those in corresponding control cells. Renal erythropoietin expression and serum erythroferrone concentration were lower in CFA-iron rats than those in control rats. In ACI rats, IV iron supplementation did not recover Hb within three days despite an increase in hepatic ferritin levels, which might be attributable to an additional increase in hepcidin levels that was already upregulated under ACI conditions. Both STAT-3 phosphorylation and SMAD1/5 phosphorylation were associated with hepcidin upregulation after IV iron treatment, and this seems to be linked to iron-induced oxidative stress.
Files in This Item:
T202105491.pdf Download
DOI
10.1155/2021/4357756
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anesthesiology and Pain Medicine (마취통증의학교실) > 1. Journal Papers
Yonsei Authors
Kwak, Young Lan(곽영란) ORCID logo https://orcid.org/0000-0002-2984-9927
Kim, Hye Bin(김혜빈) ORCID logo https://orcid.org/0000-0003-3108-8693
Shim, Jae Kwang(심재광) ORCID logo https://orcid.org/0000-0001-9093-9692
Oh, Ju Eun(오주은)
Jun, Ji Hae(전지혜) ORCID logo https://orcid.org/0000-0002-8080-0715
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187312
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