Reduction of indoxyl sulfate by AST‐120 attenuates monocyte inflammation related to chronic kidney disease. Issue 6 (29th January 2013)

• Record Type: Journal Article
• Authors: Ito, Shunsuke; Higuchi, Yusuke; Yagi, Yoko; Nishijima, Fuyuhiko; Yamato, Hideyuki; Ishii, Hideto; Osaka, Mizuko; Yoshida, Masayuki
• Is Part Of: Journal of leukocyte biology. Volume 93:Issue 6(2013)
• Page Start: 837
• Page End: 845
• Publication Date: 2013-01-29
• Subjects: uremic toxin -- atherosclerosis -- leukocyte–endothelial interactions -- adhesion molecule -- oxidative stress; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.0112023
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Indoxyl sulfate induced Mac‐1 expression and ROS production via p38 MAPK‐ and NAD(P)H oxidase‐dependent pathways. 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.