Indoxyl sulfate stimulates oxidized LDL uptake through up-regulation of CD36 expression in THP-1 macrophages

Indoxyl sulfate (IS), a uremic toxin, is considered as a risk factor for accelerated atherosclerosis in patients with chronic kidney disease. As uptake of oxidized low-density lipoprotein (Ox-LDL) in macrophages is a key event in the progression of atherosclerosis, the aim of this study was to determine direct effects of IS on uptake of Ox-LDL in macrophages. Flow cytometric analysis revealed that IS significantly stimulated Ox-LDL uptake by THP-1 macrophages in both dose- and time-dependent manners. A CD36 inhibitor, sulfosuccinimidyl oleate (SSO), and ERK1/2 inhibitors, PD98059 and U0126, could suppress the IS-stimulated Ox-LDL uptake. IS also stimulated CD36 expression, which was inhibited by PD98059 and U0126. Western blotting analysis showed that IS significantly activated ERK1/2 mitogen-activated protein kinase (MAPK) pathway by increasing its phosphorylation level. Further, CCK-8 assay showed that IS exerted its effects without affecting cell viability. In conclusion, IS stimulated Ox-LDL uptake through up-regulation of CD36 expression in THP-1 macrophages, partly via ERK1/2 MAPK pathway. This might be one of the mechanisms underlying the progression of atherosclerosis in patients with chronic kidney disease. (C) 2014 Faculty of Health and Social Studies, University of South Bohemia in Ceske Budejovice. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.