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Abstract: FR-PO478

Hypervitaminosis A Contributes to Abnormal Iron Metabolism in CKD

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic


  • Kabutoya, Serina, Tokushima university, Tokushima, Japan
  • Masuda, Masashi, Tokushima University, Tokushima, Japan
  • Adachi, Yuichiro, Tokushima University, Tokushima, Japan
  • Yimamu, Yilimulati, Tokushima university, Tokushima, Japan
  • Okumura, Hisami, University of Tokushima, Tokushima, Japan
  • Yamamoto, Hironori, Dept. of Health and Nutrition, Jin-ai University, Echizen city, Fukui, Japan
  • Taketani, Yutaka, University of Tokushima, Tokushima, Japan

Anemia is the major features of chronic kidney disease (CKD). Hepcidin (HAMP) is the principal iron regulatory hormone and its overproduction contributes to anemia. HAMP blocks iron fluxes to the blood by degradation of the iron exporter ferroportin (FPN) at the plasma membrane of macrophages. It has been reported plasma vitamin A and its metabolites, all-trans retinoic acid (ATRA), are increased in CKD patients. Several reports showed both hypervitaminosis A and vitamin A deficiency (VAD) results in iron deposition in the liver and reduces serum iron levels in rats, which suggests an inappropriate vitamin A levels may affect iron metabolism disorder. However, the molecular mechanism behind the regulation of iron metabolism by ATRA have been unclear. In this study, we investigated whether hypervitaminosis A can be involved in abnormal iron metabolism in CKD and its molecular mechanism.


Five-week-old male C57BL/6J mice were treated 5/6 nephrectomy operation to induce CKD and they were fed VAD diet for nine weeks. Iron deposition of tissues was evaluated by Berlin blue stain. Gene expressions were evaluated by RT-PCR, Western blotting.


Berlin blue stain showed VAD diet did not affect hepatic iron deposition, but reduced hepatic HAMP protein levels in CKD mice. Furthermore, VAD decreased the expression of hepatic p-STAT3 protein, transcription factor which activates HAMP transcription, in CKD mice. In spleen, VAD inhibited iron deposition and increased FPN mRNA levels in CKD mice. To understand the more detailed mechanism of abnormal iron metabolism by hypervitaminosis A, we evaluated iron-related gene expression in response to ATRA in vitro. The expression of HAMP mRNA and protein were increased by ATRA in HepG2 cells. Ro 41-5253, RAR antagonist, reduced HAMP mRNA levels increased by ATRA in HepG2 cells. Both ATRA and TTNPB, RAR agonist, increased p-STAT3 protein levels in HepG2 cells. Finally, we investigated whether VAD-increased splenic FPN mRNA expression in CKD was not only via HAMP action but also a direct action of ATRA. Interestingly, ATRA reduced the levels of FPN mRNA and protein in Raw264 cells.


We suggest CKD-induced hypervitaminosis A may contribute to abnormal iron metabolism through the indirect regulation of hepatic HAMP and the direct regulation of splenic FPN.