title: Uremic toxin indoxyl sulfate inhibits human vascular smooth muscle cell proliferation.
abstract: Uremic syndrome is attributed to the progressive retention of a large number of compounds, such as indoxyl sulfate, which under physiological conditions are excreted by the kidneys. Previous in vitro studies have demonstrated that uremic indoxyl sulfate concentrations induce a weak increase in the proliferation of both rat and human vascular aortic smooth muscle cells (hVASMC) after short term exposition to the toxin (i.e. 24 h). In the present study, we evaluated indoxyl sulfate effects on the proliferation of hVASMC at three different concentrations after long-term exposure (seven days). In contrast to previously published studies, we observed a dose-dependent and significant inhibitory effect of this toxin on hVASMC proliferation. We also demonstrated that indoxyl sulfate inhibits epidermal growth factor-induced hVASMC proliferation after long-term exposure. Indoxyl sulfate effects were associated with a dose-dependent induction of intracellular reactive oxygen species and up-regulation of p21 and p27 protein expression. Chronic exposure to indoxyl sulfate produces a significant inhibitory effect on hVASMC proliferation. The relevance of these findings must be evaluated by further studies, particularly in an in vivo setting.
authors.affiliation: French National Institute of Health and Medical Research (INSERM), ERI-12 (EA 4292), Amiens, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Mozar
authors.forename: Loïc
authors.initials: L
authors.lastname: Louvet
authors.forename: Patrice
authors.initials: P
authors.lastname: Morlière
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.forename: Cédric
authors.initials: C
authors.lastname: Boudot
authors.forename: Saïd
authors.initials: S
authors.lastname: Kamel
authors.forename: Tilman B
authors.initials: TB
authors.lastname: Drüeke
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Massy
mesh_terms: D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007200:Indican / Q000008:administration & dosage / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004815:Epidermal Growth Factor; D007200:Indican