title: Uraemic toxins induce proximal tubular injury via organic anion transporter 1-mediated uptake.
abstract: A direct effect of uraemic toxins in promoting progression of chronic renal disease has not been established. In this study, we investigated the toxic effects of organic anions which characteristically appeared in the patients with progressive renal disease on renal proximal tubular cells expressing human organic anion transporter (hOAT) 1. A renal proximal tubular cell line, opossum kidney (OK) cells, was transformed with hOAT1. Among the organic anions examined, hippuric acid, para-hydroxyhippuric acid, ortho-hydroxyhippuric acid, indoxyl sulphate and indoleacetic acid showed a high affinity for hOAT1 expressed in the OK cells. Indoxyl sulphate and indoleacetic acid concentration-dependently inhibited proliferation of the hOAT1-transformed cells. The h.p.l.c. analysis demonstrated that cellular uptake of these organic anions was significantly elevated in hOAT1-transformed cells. These organic anions also concentration-dependently stimulated cellular free radical production. The degrees of inhibition of cell proliferation and the stimulation of free radical production induced by the organic anions were significantly higher in the hOAT1-transformed cells than vector-transformed cells. The stimulatory effect of indoxyl sulphate on free radical production was abolished by anti-oxidants and probenecid. Less free radical production was observed in the hOAT1-transformed cells treated with p-hydroxyhippuric acid, o-hydroxyhippuric acid compared with indoxyl sulphate and indoleacetic acid. Hippuric acid had little effect on free radical production. Organic anions present in the serum of patients with progressive renal disease may cause proximal tubular injury via hOAT1-mediated uptake. The mechanism of cellular toxicity by these uraemic toxins involves free radical production. Thus, some uraemic toxins may directly promote progression of chronic renal disease.
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, School of Medicine, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Motojima
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hosokawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamato
authors.forename: Takamura
authors.initials: T
authors.lastname: Muraki
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yoshioka
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D005609:Free Radicals / Q000378:metabolism; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009893:Opossums; D027362:Organic Anion Transport Protein 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D014118:Toxins, Biological / Q000378:metabolism / Q000494:pharmacology*; D014511:Uremia / Q000378:metabolism*; D010130:p-Aminohippuric Acid / Q000494:pharmacology
chemical_list: D005609:Free Radicals; D006131:Growth Inhibitors; D027362:Organic Anion Transport Protein 1; D014118:Toxins, Biological; D010130:p-Aminohippuric Acid