Reduction of indoxyl sulfate by AST-120 attenuates monocyte inflammation related to chronic kidney disease.
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.
Department of International Health Development, Tokyo Medical and Dental University, Tokyo, Japan.
Shunsuke
S
Ito
Yusuke
Y
Higuchi
Yoko
Y
Yagi
Fuyuhiko
F
Nishijima
Hideyuki
H
Yamato
Hideto
H
Ishii
Mizuko
M
Osaka
Masayuki
M
Yoshida
D000818:Animals; D002244:Carbon / Q000494:pharmacology*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007200:Indican / Q000378:metabolism*; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000276:immunology / Q000378:metabolism*
D005765:Gastrointestinal Agents; D010087:Oxides; D017382:Reactive Oxygen Species; D002244:Carbon; C040896:AST 120; D007200:Indican
adhesion molecule; atherosclerosis; leukocyte–endothelial interactions; oxidative stress; uremic toxin