• DOI:10.1093/ndt/gfv250
• Corpus ID: 11071281

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

@article{Ochi2015IndoxylSS,
  title={Indoxyl sulfate suppresses hepatic fetuin-A expression via the aryl hydrocarbon receptor in HepG2 cells.},
  author={Akinobu Ochi and Katsuhito Mori and Shinya Nakatani and Masanori Emoto and Tomoaki Morioka and Koka Motoyama and Shinya Fukumoto and Yasuo Imanishi and Tetsuo Shoji and Eiji Ishimura and Masaaki Inaba},
  journal={Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association},
  year={2015},
  volume={30 10},
  pages={
          1683-92
        }
}

• Akinobu Ochi, K. Mori, +8 authors M. Inaba
• Published 1 October 2015
• Medicine, Biology, Chemistry
• Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association

BACKGROUND
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.

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

RESULTS
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 IS-induced fetuin-A suppression. Then, because IS is a potent endogenous ligand of the aryl hydrocarbon receptor (AhR), we assessed whether IS suppresses fetuin-A production via AhR. The knockdown of AhR prevented IS-induced fetuin-A suppression. However, some attention should be paid to no effect of IS on fetuin-A expression in mouse and human primary cultured hepatocytes.

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