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. 2013 Jun;93(6):837-45.
doi: 10.1189/jlb.0112023. Epub 2013 Jan 29.

Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease

Shunsuke Ito  1 , Yusuke Higuchi, Yoko Yagi, Fuyuhiko Nishijima, Hideyuki Yamato, Hideto Ishii, Mizuko Osaka, Masayuki Yoshida
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Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease

Shunsuke Ito et al. J Leukoc Biol. 2013 Jun.

Abstract

Accelerated cardiovascular disease is a frequent complication of CKD. Monocyte-mediated inflammation and adhesion of monocytes to vascular endothelium are key events in atherogenesis. An oral adsorbent, AST-120, retards renal function deterioration by lowering IS, which is known to accumulate in CKD patients. However, the effect of AST-120 on CKD-related monocyte activation is unknown. We aimed to determine whether AST-120 improves monocyte-mediated inflammation through IS reduction. Flow cytometric analysis showed that Mac-1 expression and ROS production were significantly higher in peripheral blood monocytes of subtotal Nx CKD mice than in sham-operated mice. AST-120 treatment significantly decreased Mac-1 expression and ROS production in CKD model mice. Furthermore, administration of IS induced monocyte-mediated inflammation and ROS generation. In vitro studies indicated that IS dose-dependently increased THP-1 monocytic cell adhesion to IL-1β-activated HUVECs under physiological flow conditions. IS also induced monocyte-mediated inflammation and ROS production in THP-1 cells. Phosphorylation of p38 MAPK and membrane translocation of NAD(P)H oxidase subunit p47phox in THP-1 cells were induced by IS. Both SB203580 (p38 MAPK inhibitor) and apocynin [NAD(P)H oxidase inhibitor] reduced THP-1 cell adhesion to HUVECs. Apocynin also inhibited IS-induced ROS production in THP-1 cells. IS induced monocyte-driven inflammation through NAD(P)H oxidase- and p38 MAPK-dependent pathways in monocytes. The main finding of this study was that AST-120 inhibited monocyte activation by reducing IS in vivo. This provides new insights on how AST-120 attenuates the progression of atherosclerosis in CKD.

Keywords: adhesion molecule; atherosclerosis; leukocyte–endothelial interactions; oxidative stress; uremic toxin.

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