Abstract: FR-PO349

Indoxyl Sulfate Disturbs Normal Iron Metabolism via Hepcidin Upregulation in CKD

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Hamano, Hirofumi, Tokushima University Graduate School, Tokushima City, Japan
  • Ikeda, Yasumasa, Tokushima University Graduate School, Tokushima City, Japan
  • Horinouchi, Yuya, Tokushima University Graduate School, Tokushima City, Japan
  • Izawa-ishizawa, Yuki, Tokushima University Graduate School, Tokushima City, Japan
  • Kagami, Shoji, Tokushima University Hospital, Tokushima City, Japan
  • Tamaki, Toshiaki, Tokushima University Graduate School, Tokushima City, Japan
Background

Hepcidin, a secreted hormone derived from hepatocytes, is a key regulator of systemic iron metabolism to regulate iron efflux from intracellular iron by the internalization and degradation of ferroportin (FPN). Hepcidin concentration is increased in patients with chronic kidney disease (CKD), suggesting to the dysregulation of iron metabolism in CKD. Levels of indoxyl sulfate (IS), a uremic toxin, is elevated during the course of CKD progression, and its accumulation exacerbates the status of CKD. However, the role of IS accumulation on iron metabolism has remained unclear. In the present study, we investigated the involvement of IS on iron metabolism.

Methods

In in vitro experiments, HepG2 cells were used to examine the mechanism of IS on hepcidin regulation. We used a mouse model of adenine-induced CKD to analyze hepcidin action on body iron metabolism in in vivo. The CKD mice were divided into two groups: one was treated using AST-120 (uremic toxin adsorbent) and the other received no treatment. In addition, we tested mice with direct IS administration.

Results

In in vitro experiments using HepG2 cells, IS augmented hepcidin expression in a dose-dependent manner. IS-induced hepcidin upregulation was inhibited by silencing or pharmacological inhibition of aryl hydrocarbon receptor (AhR), a receptor of IS. IS also augmented oxidative stress and anti-oxidant drugs suppressed IS-induced hepcidin upregulation. Adenine-induced CKD mice showed the elevation of hepatic hepcidin mRNA expression and blood hepcidin concentration compared with control mice. In CKD mice, renal anemia, decreased blood iron concentration, increased blood ferritin levels, and increased splenic iron content were seen, and ferroportin was decreased in the duodenum and increased in the spleen. These changes were ameliorated by AST-120 treatment. CKD mice showed iron-deficient anemia, and this was slightly ameliorated by AST-120 treatment. Moreover, mice treated by direct IS administration showed hepatic hepcidin upregulation.

Conclusion

IS participates in the dysregulation of iron metabolism through hepcidin regulation via AhR and oxidative stress in CKD. Removal of IS might be a therapeutic strategy for abnormality of iron metabolism in CKD.