Pharmaceutical Research

, Volume 24, Issue 7, pp 1283–1289 | Cite as

An Oral Adsorbent, AST-120 Protects Against the Progression of Oxidative Stress by Reducing the Accumulation of Indoxyl Sulfate in the Systemic Circulation in Renal Failure

  • Kazuki Shimoishi
  • Makoto Anraku
  • Kenichiro Kitamura
  • Yuka Tasaki
  • Kazuaki Taguchi
  • Mitsuru Hashimoto
  • Eiko Fukunaga
  • Toru Maruyama
  • Masaki Otagiri
Research Paper

Abstract

Purpose

The effect of AST-120, an oral adsorbent, on oxidative stress in the systemic circulation in chronic renal failure (CRF) was examined and the potential role of indoxyl sulfate (IS), an uremic toxin adsorbed by AST-120, in inducing the formation of reactive oxygen species (ROS) in the vascular system was studied, in vitro and in vivo.

Materials and methods

The level of oxidized albumin, a marker for oxidative stress in the systemic circulation was determined by HPLC, as previously reported. The mRNA levels of TGF-β1 and Oat1 were measured by quantitative RT-PCR. The IS induced ROS generation in cultured human umbilical vein endothelial cells (HUVECs) was estimated using a fluorescence microplate reader.

Results

An increase in the ratio of oxidized to unoxidized albumin was determined using 5/6 nephrectomized rats (CRF rats) compared to a control group. The ratio was significantly reduced in the group that received AST-120 of 4 weeks, suggesting that AST-120 inhibits oxidative stress in CRF. An anti-oxidative effect of AST-120 was also observed in CRF rats with a similar renal function. The ratio of oxidized albumin was correlated with serum IS levels in vivo. The same relationship was also observed in CRF rats with the continued administration of IS. In addition, IS dramatically increased the generation of ROS in both a dose- and time- dependent manner in HUVEC, suggesting that accumulated IS may play an important role in enhancing intravascular oxidative stress.

Conclusion

We propose that AST-120 reduces IS concentrations in the blood that induces ROS production in endothelial cells, thereby inhibiting the subsequent occurrence of oxidative stress in the systemic circulation in renal failure.

Key words

albumin oxidation AST-120 chronic renal failure indoxyl sulfate 

Abbreviations

CRF

chronic renal failure

CVD

cardiovascular disease

HPLC

high-performance liquid chromatography

HSA

human serum albumin

HUVEC

human umbilical vein endothelial cell

IS

indoxyl sulfate

OAT

organic anion transporter

ROS

reactive oxygen spiecies

TGF-β1

transforming growth factor-β1

TIMP-1

tissue inhibitor of metalloproteinease

Notes

Acknowledgements

We wish to thank the KUREHA CORPORATION (Tokyo, Japan) for the generous gift of AST-120.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Kazuki Shimoishi
    • 1
    • 4
  • Makoto Anraku
    • 1
  • Kenichiro Kitamura
    • 2
  • Yuka Tasaki
    • 1
  • Kazuaki Taguchi
    • 1
  • Mitsuru Hashimoto
    • 3
  • Eiko Fukunaga
    • 4
  • Toru Maruyama
    • 1
  • Masaki Otagiri
    • 1
  1. 1.Department of Biopharmaceutics, Graduate School of Pharmaceutical SciencesKumamoto University KumamotoJapan
  2. 2.Department of Nephrology, Graduate School of Medical SciencesKumamoto UniversityKumamotoJapan
  3. 3.Department of Pathopharmacology, Graduate School of Pharmaceutical SciencesKumamoto UniversityKumamotoJapan
  4. 4.Department of Pharmacy, Japanese Red CrossKumamoto HospitalKumamotoJapan

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