Indoxyl sulfate stimulates monocyte chemoattractant protein-1 expression in human umbilical vein endothelial cells by inducing oxidative stress through activation of the NADPH oxidase-nuclear factor-κB pathway.

Abstract

BACKGROUND:

Chronic kidney disease (CKD) is recognized as a common condition that elevates the risk of atherosclerotic cardiovascular disease (CVD). Evidence suggests that increased oxidative stress is an emerging key mechanism of atherosclerosis in CKD. One recent study reported that indoxyl sulfate (IS), a uremic toxin derived from dietary protein, could cause vascular disorder, however, little is known about the mechanism involved. The present study examined the signaling pathway that is activated by IS to induce monocyte chemoattractant protein-1 (MCP-1), which plays an important role in the development of atherosclerosis, in cultured human umbilical vein endothelial cells (HUVEC).

METHODS AND RESULTS:

We show that IS enhanced reactive oxygen species (ROS) production, assessed by dihydroethidium staining, by HUVEC. IS also induced the expression of MCP-1, which was measured by enzyme-linked immunosorbent assay and real-time reverse transcription-polymerase chain reaction. These changes were suppressed by apocynin, a specific inhibitor of NADPH oxidase. Furthermore, IS induced the expression of NADPH oxidase 4 (Nox4) mRNA. IS-induced stimulation of ERK1/2 and p38 phosphorylation, detected by immunoblotting, was inhibited by apocynin. Finally, IS activated NF-κB, which was suppressed by inhibiting ERK1/2 and p38, resulting in reduced MCP-1 expression. These results suggest that IS increases NADPH oxidase-derived ROS, which in turn, activates the MAPK/NF-κB pathway and leads to induction of MCP-1 expression in HUVEC.

CONCLUSIONS:

These findings raise the possibility that IS plays an important pathophysiological role in the development of CVD in individuals with CKD.

• Authors: Natsumi Masai, Junko Tatebe, Gen Yoshino, Toshisuke Morita
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 74 Issue 10 Pg. 2216-24 (Oct 2010) ISSN: 1347-4820 [Electronic] Japan
• PMID: 20818133 (Publication Type: Journal Article)

Chemical References

• Chemokine CCL2
• NF-kappa B
• NADPH Oxidases
• Indican

Topics

• Atherosclerosis (etiology)
• Cells, Cultured
• Chemokine CCL2 (biosynthesis, drug effects)
• Endothelial Cells (metabolism)
• Humans
• Indican (pharmacology)
• NADPH Oxidases (metabolism)
• NF-kappa B (metabolism)
• Oxidative Stress (drug effects)
• Renal Insufficiency, Chronic (complications)
• Signal Transduction (drug effects)
• Umbilical Veins (cytology)