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

Journal of Leukocyte Biology

Shunsuke Ito³  Hideyuki Yamato¹  Yusuke Higuchi¹  Masayuki Yoshida²  Yoko Yagi¹  Fuyuhiko Nishijima¹  Hideto Ishii²  Mizuko Osaka and² 

[1]  Biomedical Research Laboratories, Kureha Corporation, Tokyo, Japan Life Science and Bioethics, Department of International Health Development, Tokyo Medical and Dental University, Tokyo, Japan;Life Science and Bioethics, Department of International Health Development, Tokyo Medical and Dental University, Tokyo, Japan;;Life Science and Bioethics, Department of International Health Development, Tokyo Medical and Dental University, Tokyo, Japan; and  Biomedical Research Laboratories, Kureha Corporation, Tokyo, Japan

关键词: uremic toxin;    atherosclerosis;    leukocyte–endothelial interactions;    adhesion molecule;    oxidative stress;   

DOI  :  10.1189/jlb.0112023

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown