title: p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase.
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.
authors: Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Hiroshi
authors: H
authors: Watanabe
authors: Yohei
authors: Y
authors: Miyamoto
authors: Daisuke
authors: D
authors: Honda
authors: Hisae
authors: H
authors: Tanaka
authors: Qiong
authors: Q
authors: Wu
authors: Masayuki
authors: M
authors: Endo
authors: Tsuyoshi
authors: T
authors: Noguchi
authors: Daisuke
authors: D
authors: Kadowaki
authors: Yu
authors: Y
authors: Ishima
authors: Shunsuke
authors: S
authors: Kotani
authors: Makoto
authors: M
authors: Nakajima
authors: Keiichiro
authors: K
authors: Kataoka
authors: Shokei
authors: S
authors: Kim-Mitsuyama
authors: Motoko
authors: M
authors: Tanaka
authors: Masafumi
authors: M
authors: Fukagawa
authors: Masaki
authors: M
authors: Otagiri
authors: Toru
authors: T
authors: Maruyama
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003408:Cresols / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009392:Nephrectomy; D018384:Oxidative Stress / Q000187:drug effects*; D011339:Probenecid / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013463:Sulfuric Acid Esters / Q000633:toxicity*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D003408:Cresols; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013463:Sulfuric Acid Esters; C508960:TGFB1 protein, human; C560822:TIMP1 protein, human; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; C408690:4-cresol sulfate; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; C498911:Nox4 protein, rat; C086986:CYBA protein, human; C515768:Cyba protein, rat; D011339:Probenecid