Abstract
The accumulation of p-cresyl sulfate (PCS), a uremic toxin, is associated with the mortality rate of chronic kidney disease patients; however, the biological functions and the mechanism of its action remain largely unknown. Here we determine whether PCS enhances the production of reactive oxygen species (ROS) in renal tubular cells resulting in cytotoxicity. PCS exhibited pro-oxidant properties in human tubular epithelial cells by enhancing NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) activity. PCS also upregulated mRNA levels of inflammatory cytokines and active TGF-β1 protein secretion associated with renal fibrosis. Knockdown of p22(phox) or Nox4 expression suppressed the effect of PCS, underlining the importance of NADPH oxidase activation on its mechanism of action. PCS also reduced cell viability by increasing ROS production. The toxicity of PCS was largely suppressed in the presence of probenecid, an organic acid transport inhibitor. Administration of PCS for 4 weeks caused significant renal tubular damage in 5/6-nephrectomized rats by enhancing oxidative stress. Thus, the renal toxicity of PCS is attributed to its intracellular accumulation, leading to both increased NADPH oxidase activity and ROS production, which, in turn, triggers induction of inflammatory cytokines involved in renal fibrosis. This mechanism is similar to that for the renal toxicity of indoxyl sulfate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cell Survival / drug effects
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Collagen Type I / metabolism
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Collagen Type I, alpha 1 Chain
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Cresols / toxicity*
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Cytokines / genetics
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Enzyme Activation
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Epithelial Cells / drug effects*
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Epithelial Cells / enzymology
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Epithelial Cells / pathology
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Fibrosis
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Humans
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Inflammation Mediators / metabolism
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Kidney Tubules, Proximal / drug effects*
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Kidney Tubules, Proximal / enzymology
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Kidney Tubules, Proximal / pathology
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Male
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NADPH Oxidase 4
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NADPH Oxidases / genetics
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NADPH Oxidases / metabolism*
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Nephrectomy
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Oxidative Stress / drug effects*
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Probenecid / pharmacology
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RNA Interference
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Reactive Oxygen Species / metabolism
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Renal Insufficiency, Chronic / chemically induced*
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Renal Insufficiency, Chronic / enzymology
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Renal Insufficiency, Chronic / genetics
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Renal Insufficiency, Chronic / pathology
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Sulfuric Acid Esters / toxicity*
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Transfection
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Transforming Growth Factor beta1 / metabolism
Substances
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Collagen Type I
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Collagen Type I, alpha 1 Chain
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Cresols
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Cytokines
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Inflammation Mediators
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RNA, Messenger
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Reactive Oxygen Species
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Sulfuric Acid Esters
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TGFB1 protein, human
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TIMP1 protein, human
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Tgfb1 protein, rat
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Tissue Inhibitor of Metalloproteinase-1
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Transforming Growth Factor beta1
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4-cresol sulfate
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NADPH Oxidase 4
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NADPH Oxidases
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NOX4 protein, human
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Nox4 protein, rat
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CYBA protein, human
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Cyba protein, rat
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Probenecid