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.
OBJECTIVE
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.


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-beta (1) 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.


CONCLUSIONS
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.
Shimoishi
Kazuki
K
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto, Japan.
Anraku
Makoto
M
Kitamura
Kenichiro
K
Tasaki
Yuka
Y
Taguchi
Kazuaki
K
Hashimoto
Mitsuru
M
Fukunaga
Eiko
E
Maruyama
Toru
T
Otagiri
Masaki
M
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002244:Carbon / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007200:Indican / Q000097:blood* / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009392:Nephrectomy; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000975:Antioxidants; D015415:Biomarkers; D027362:Organic Anion Transport Protein 1; D010087:Oxides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D012709:Serum Albumin; C421043:Slc22a6 protein, rat; D053773:Transforming Growth Factor beta1; D002244:Carbon; C040896:AST 120; D007200:Indican