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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/C389    most recent 00206.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shimizu, H. Articles by Miyazaki, H. PubMed PubMed Citation Articles by Shimizu, H. Articles by Miyazaki, H.

VASCULAR BIOLOGY

ROS and PDFG-β receptors are critically involved in indoxyl sulfate actions that promote vascular smooth muscle cell proliferation and migration

¹Graduate School of Life and Environment Sciences, Alliance for Research on North Africa, University of Tsukuba, Ibaraki; ²Medicinal Adsorbent Department, Biomedical Research Laboratories, Kureha Corporation, Tokyo; and ³Department of Nephrology Osaka General Medical Center, Osaka Prefecture Hospital Organization, Osaka, Japan

Submitted 11 May 2009 ; accepted in final form 2 June 2009

Patients with chronic renal failure are at greater risk of developing atherosclerosis than healthy individuals, and recent data suggest that the putative uremic toxin indoxyl sulfate (IS) promotes the pathogenesis of atherosclerosis. The present study examined the effects of IS on vascular smooth muscle cells (VSMCs) with respect to reactive oxygen species (ROS), platelet-derived growth factor (PDGF) receptors, and mitogen-activated protein kinases (MAPKs). IS induced the migration and proliferation of VSMCs and synergistically enhanced their PDGF-induced migration as well as proliferation. The effects of PDGF were promoted after a 24-h incubation with IS despite the absence of IS during PDGF stimulation. Intracellular ROS levels were increased in the presence of IS, and PDGF-dependent ROS production was augmented by a prior 24-h incubation with IS even in the absence of IS during PDGF stimulation. These data suggest that IS increases the sensitivity of VSMCs to PDGF. IS also phosphorylated PDGF-β-receptors and upregulated PDGF-β receptor but not -receptor protein expression in the absence of exogenous PDGF. The NADPH oxidase inhibitor diphenylene iodonium blocked IS-dependent increase in receptor expression. Administration of IS to nephrectomized rats also elevated receptor protein expression in arterial VSMCs. Inhibitors of NADPH oxidase, PDGF-β receptors, extracellular-regulated protein kinase (ERK), and p38 MAPK all inhibited IS-induced VSMCs migration and proliferation. Taken together, these findings indicate that IS induces the migration as well as proliferation of VSMCs through PDGF-β receptors and that ROS generation is critically involved in this process, which promotes the development of atherosclerosis.

uremic toxin; chronic renal failure; atherosclerosis; reactive oxygen species; platelet-derive growth factor-β