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Indoxyl Sulfate Involves Abnormality of Iron Metabolism Through Hepcidin Regulation
Author(s) -
Hamano Hirofumi,
Ikeda Yasumasa,
Watanabe Hiroaki,
Horinouchi Yuya,
IzawaIshizawa Yuki,
Ishizawa Keisuke,
Tsuchiya Koichiro,
Tamaki Toshiaki
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.667.11
Subject(s) - hepcidin , ferroportin , endocrinology , medicine , downregulation and upregulation , metabolism , oxidative stress , chemistry , inflammation , aryl hydrocarbon receptor , kidney disease , biology , biochemistry , gene , transcription factor
Background Hepcidin, a secreted hormone derived from hepatocytes, a key regulator of iron metabolism, is shown to be elevated in chronic kidney disease (CKD), leading to the dysregulation of iron metabolism in CKD. Indoxyl sulfate (IS), a uremic toxin, is accumulated during the progression of CKD, and it exacerbates CKD through oxidative stress and inflammation. However, the role of IS on iron metabolism has remained unclear. In the present study, we investigated the involvement of IS on iron metabolism. Methods In in vitro , HepG2 cells were used to examine IS effect on hepcidin. In in vivo , we analyzed hepcidin, iron transporters, and tissue iron content by using a mice model of CKD. In addition, we investigated whether CKD‐induced iron dysmetabolism was ameliorated by AST‐120, uremic toxin adsorbent. Results IS stimulation augmented hepcidin expression in a dose‐dependent manner in HepG2 cells. IS‐mediated hepcidin upregulation was inhibited by silencing of aryl hydrocarbon receptor (AhR), a receptor of IS. IS also augmented oxidative stress and hepcidin upregulation with IS was suppressed by an anti‐oxidant agent. CKD mice with increased IS accumulation showed the elevation of hepatic hepcidin expression and blood hepcidin concentration compared with control mice. In CKD mice, ferroportin expression was changed in duodenum and spleen, and splenic iron content was increased. These changes were ameliorated by AST‐120 treatment. Conclusion Our study suggested that IS participates in the dysregulation of iron metabolism through hepcidin regulation. Removal of IS from plasma might be a therapeutic strategy for abnormality of iron metabolism in CKD.