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Figure 4. Tranilast inhibits urate transport mediated by the human urate transporter OAT10. (A) Time course of [14C]‐urate uptake by control and URAT1‐expressing oocytes. [14C]‐urate uptake by OAT10‐expressing oocytes was trans‐stimulated by preinjecting with 50 nL of 100 mmol/L PZA 2 h. Inset, western blot analysis of OAT10 protein expressed in oocytes. (B) Trans‐stimulatory effects of preloaded organic anions on [14C]‐urate uptake by OAT10‐expressing oocytes: [14C]‐urate uptake rate mediated by OAT10 was measured in OAT10‐expressing oocytes preloaded with 50 nL of 100 mmol/L Lac, Nico, PZA, PAH, BHB, α‐ketoglutarate (α‐KG) or succinate (Succi). *P < 0.001 compared with water‐injected control. (C) [14C]‐urate transport properties of OAT10: voltage sensitivity and Na+‐dependence was examined by replacing extracellular NaCl by KCl or LiCl. Existence of urate/Cl− exchange mechanism or Cl− dependence or cis‐inhibitory effects of extracellular Cl− on was verified by [14C]‐urate uptake via OAT10 in the absence of extracellular Cl− ion (0 Cl−). In 0 Cl− bath, NaCl was replaced by Na‐gluconate (Na‐Gluc), KCl by k‐gluconate (K‐Gluc), MgCl2 by Mg‐gluconate, and CaCl2 by Ca‐gluconate. Asterisk, P < 0.001 compared with NaCl (ND96); NS, not significant. (D) Inhibition of [14C]‐urate by OAT10 in the presence of extracellular organic anions or uricosuric drugs: The uptake of [14C]‐urate (40 μmol/L) by OAT10‐expressing oocytes in exchange of preloaded intracellular PZA was determined after 1 h in the absence or presence of inhibitors (uricosuric drugs) that were added to the extracellular medium at the indicated concentrations. *P < 0.001 compared with NaCl (ND96). Tran, Benz, Prob, DMSO. Data are mean ± S.E. with n = 12–15. (E) The 50% inhibitory concentration (IC 50) curve of tranilast for [14C]‐urate uptake via OAT10 in oocytes preloaded with PZA. PZA, pyrazine carboxylate; PAH, para‐aminohippurate; Lac, lactate; Nico, nicotinate; PZA, pyrazine carboxylate; Tran, tranilast; Benz, benzbromarone; Prob, probenecid; DMSO, dimethylsulfoxide. Image published in: Mandal AK et al. (2017) © 2017 The Authors. This image is reproduced with permission of the journal and the copyright holder. This is an open-access article distributed under the terms of the Creative Commons Attribution license Larger Image Printer Friendly View

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