Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells.

Journal Reference

Ochi A1, Mori K1, Nakatani S1, Emoto M1, Morioka T1, Motoyama K1, Fukumoto S1, Imanishi Y1, Shoji T2, Ishimura E1, Inaba M1.

 [expand title=”Show Affiliations”]

  1. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
  2. Department of Geriatrics and Vascular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.[/expand]



Fetuin-A is a liver-derived circulating protein that has potent calcification-inhibitory activity. Uraemic patients exhibit decreased serum fetuin-A levels, increased vascular calcification and elevated cardiovascular mortality. Because the mechanisms for fetuin-A deficiency are unknown, we hypothesized that some uraemic toxins suppressed hepatic fetuin-A production, which resulted in accelerated vascular calcification and poor outcome. Among these potential candidates, indoxyl sulfate (IS) has highly toxic properties.


We examined the direct effects of Indoxyl sulfate on hepatic fetuin-A expression using the human hepatoma HepG2 cell line.


IS, but not p-cresyl sulfate, suppressed the mRNA and protein expression of fetuin-A in a dose- and time-dependent manner. As reported previously, IS stimulated p38 MAPK phosphorylation and reactive oxygen species (ROS) production, although the knockdown of p38 and inhibition of ROS generation had no effect on Indoxyl sulfate induced fetuin-A suppression. Then, because Indoxyl sulfate is a potent endogenous ligand of the aryl hydrocarbon receptor(AhR), we assessed whether Indoxyl sulfate  suppresses fetuin-A production via AhR. The knockdown of AhR prevented Indoxyl sulfate -induced fetuin-A suppression. However, some attention should be paid to no effect of Indoxyl sulfate  on fetuin-A expression in mouse and human primary cultured hepatocytes.


These findings suggest that Indoxyl sulfate  could suppress hepatic fetuin-A expression by activating AhR, suggesting a relationship between uraemia and fetuin-A deficiency.

© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Go To Nephrol Dial Transplant