Indoxyl sulfate upregulates expression of ICAM-1 and MCP-1 by oxidative stress-induced NF-kappaB activation.
OBJECTIVE
Indoxyl sulfate, a uremic toxin, is considered a risk factor for cardiovascular disease (CVD) in chronic kidney disease (CKD). The present study aimed to determine whether indoxyl sulfate increases the expression of intercellular adhesion molecule-1 (ICAM-1) and monocyte chemotactic protein-1 (MCP-1) by reactive oxygen species (ROS)-induced activation of nuclear factor-kappaB (NF-kappaB) in vascular endothelial cells.


METHODS
Human umbilical vein endothelial cells (HUVEC) were incubated with indoxyl sulfate. The expression of ICAM-1 and MCP-1 in HUVEC was analyzed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. Phospho-NF-kappaB p65 (Ser 536), an active form of the NF-kappaB subunit, was determined by Western blotting.


RESULTS
Indoxyl sulfate significantly increased the mRNA expression of ICAM-1 and MCP-1 in HUVEC in a time- and concentration-dependent manner. Inhibitors of NF-kappaB (ammonium pyrrolidinedithiocarbamate and isohelenin) and an antioxidant (N-acetyl-L-cysteine) suppressed the indoxyl sulfate-induced expression of ICAM-1 and MCP-1 in HUVEC. Indoxyl sulfate increased phospho- NF-kappaB p65 in HUVEC, and N-acetyl-L-cysteine suppressed it.


CONCLUSIONS
Indoxyl sulfate upregulates the expression of ICAM-1 and MCP-1 by ROS-induced activation of NF-kappaB in vascular endothelial cells. Thus, indoxyl sulfate may play an important role in the development of CVD in CKD by increasing the endothelial expression of ICAM-1 and MCP-1.
Tumur
Zohra
Z
Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Shimizu
Hidehisa
H
Enomoto
Atsushi
A
Miyazaki
Hitoshi
H
Niwa
Toshimitsu
T
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation; D006801:Humans; D007200:Indican / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species; D013997:Time Factors
D000975:Antioxidants; D018932:Chemokine CCL2; D016328:NF-kappa B; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018799:Intercellular Adhesion Molecule-1; D007200:Indican; D000111:Acetylcysteine