Abstract
Organic anions (OAs) are secreted in renal proximal tubules in two steps. In the first step, OAs are transported from the blood through basolateral membranes into proximal tubular cells. The prototypical substrate for renal organic anion transport systems, para-aminohippurate (PAH), is transported across basolateral membranes of proximal tubular cells via OAT1 (SLC22A6) and OAT3 (SLC22A8) against an electrochemical gradient in exchange for intracellular dicarboxylates. In the second step, OAs exit into urine through apical membranes of proximal tubules. This step is thought to be performed by multidrug efflux transporters and a voltage-driven organic anion transporter. However, the molecular nature and precise functional properties of these efflux systems are largely unknown. Recently, we characterized an orphan transporter known as human type I sodium-phosphate transporter 4, hNPT4 (SLC17A3), using the Xenopus oocyte expression system. hNPT4 acts as a voltage-driven efflux transporter (“human OATv1”) for several OAs such as PAH, estrone sulfate, diuretic drugs, and urate. Here, we describe a model for an OA secretory pathway in renal tubular cells in which OAs exit cells and enter the tubular lumen via hOATv1 (hNPT4). Additionally, hOATv1 functions as a common renal secretory pathway for both urate and drugs, indicating that hOATv1 may be a leak pathway for excess urate that is reabsorbed via apical URAT1 to control the intracellular urate levels. Therefore, we propose a molecular mechanism for the induction of hyperuricemia by diuretics: the diuretics enter proximal tubular cells via basolateral OAT1 and/or OAT3 and may then interfere with the NPT4-mediated apical urate efflux in the renal proximal tubule.
Similar content being viewed by others
References
Anzai N, Endou H (2007) Drug transport in the kidney. In: You G, Morris ME (eds) Drug transporters: molecular characterization and role in drug disposition. Wiley, Hoboken, pp 463–493
Anzai N, Endou H (2012) Renal basis of hyperuricemia. In: Terkeltaub R (ed) Gout and other crystal arthropathies. Elsevier Saunders, Philadelphia, pp 51–58
Anzai N, Kanai Y, Endou H (2006) Organic anion transporter family: current knowledge. J Pharmacol Sci 100:411–426
Anzai N, Ichida K, Jutabha P, Kimura T, Babu E, Jin CJ, Srivastava S, Kitamura K, Hisatome I, Endou H, Sakurai H (2008) Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans. J Biol Chem 283:26834–26838
Anzai N, Jutabha P, Endou H (2010) Molecular mechanism of ochratoxin a transport in the kidney. Toxins (Basel) 2:1381–1398
Caulfield MJ, Munroe PB, O’Neill D, Witkowska K, Charchar FJ, Doblado M, Evans S, Eyheramendy S, Onipinla A, Howard P, Shaw-Hawkins S, Dobson RJ, Wallace C, Newhouse SJ, Brown M, Connell JM, Dominiczak A, Farrall M, Lathrop GM, Samani NJ, Kumari M, Marmot M, Brunner E, Chambers J, Elliott P, Kooner J, Laan M, Org E, Veldre G, Viigimaa M, Cappuccio FP, Ji C, Iacone R, Strazzullo P, Moley KH, Cheeseman C (2008) SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 5:e197
Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H (2000) Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem 275:4507–4512
Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H (2001) Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharm 59:1277–1286
Dehghan A, Köttgen A, Yang Q, Hwang SJ, Kao WL, Rivadeneira F, Boerwinkle E, Levy D, Hofman A, Astor BC, Benjamin EJ, van Duijn CM, Witteman JC, Coresh J, Fox CS (2008) Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study. Lancet 372:1953–1961
Ellison DH, Wilcox CS (2008) Brenner and Rector’s the kidney, 8th edn. Saunders Elsevier, Philadelphia, pp 1646–1678
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H (2002) Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 23:447–452
Ford JM, Hait WN (1990) Pharmacology of drugs that alter multidrug resistance in cancer. Pharmacol Rev 42:155–199
Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L, International Transporter Consortium (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236
Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58
Hosoyamada M, Sekine T, Kanai Y, Endou H (1999) Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol Renal Physiol 276:F122–F128
Jacquemin E, Hagenbuch B, Stieger B, Wolkoff AW, Meier PJ (1994) Expression cloning of a rat liver Na+-independent organic anion transporter. Proc Natl Acad Sci USA 91:133–137
Jutabha P, Kanai Y, Hosoyamada M, Chairoungdua A, Kim DK, Iribe Y, Babu E, Kim JY, Anzai N, Chatsudthipong V, Endou H (2003) Identification of a novel voltage-driven organic anion transporter present at apical membrane of renal proximal tubule. J Biol Chem 278:27930–27938
Jutabha P, Anzai N, Kitamura K, Taniguchi A, Kaneko S, Yan K, Yamada H, Shimada H, Kimura T, Katada T, Fukutomi T, Tomita K, Urano W, Yamanaka H, Seki G, Fujita T, Moriyama Y, Yamada A, Uchida S, Wempe MF, Endou H, Sakurai H (2010) Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem 285:35123–35132
Jutabha P, Anzai N, Kimura T, Taniguchi A, Urano W, Yamanaka H, Endou H, Sakurai H (2011a) Functional analysis of human sodium-phosphate transporter 4 (NPT4/SLC17A3) polymorphisms. J Pharmacol Sci 115:249–253
Jutabha P, Anzai N, Wempe MF, Wakui S, Endou H, Sakurai H (2011b) Apical voltage-driven urate efflux transporter NPT4 in renal proximal tubule. Nucleosides Nucleotides Nucleic Acids 30:1302–1311
Melis D, Havelaar AC, Verbeek E, Smit GP, Benedetti A, Mancini GM, Verheijen F (2004) NPT4, a new microsomal phosphate transporter: mutation analysis in glycogen storage disease type Ic. J Inherit Metab Dis 27:725–733
Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, Abe M, Satoh F, Unno M, Hishinuma T, Inui K, Ito S, Goto J, Abe T (2004) Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci USA 101:3569–3574
Møller JV, Sheikh MI (1982) Renal organic anion transport system: pharmacological, physiological, and biochemical aspects. Pharmacol Rev 34:315–358
Pascual E, Perdiguero M (2006) Gout, diuretics and the kidney. Ann Rheum Dis 65:981–982
Ravnan SL, Ravnan MC, Deedwania PC (2002) Pharmacotherapy in congestive heart failure: diuretic resistance and strategies to overcome resistance in patients with congestive heart failure. Congest Heart Fail 8:80–85
Reimer RJ, Edwards RH (2004) Organic anion transport is the primary function of the SLC17/type I phosphate transporter family. Pflugers Arch 447:629–635
Ruddy DA, Kronmal GS, Lee VK, Mintier GA, Quintana L, Domingo R Jr, Meyer NC, Irrinki A, McClelland EE, Fullan A, Mapa FA, Moore T, Thomas W, Loeb DB, Harmon C, Tsuchihashi Z, Wolff RK, Schatzman RC, Feder JN (1997) A 1.1-Mb transcript map of the hereditary hemochromatosis locus. Genome Res 7:441–456
Russel FG, Masereeuw R, van Aubel RA (2002) Molecular aspects of renal anionic drug transport. Annu Rev Physiol 64:563–594
Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H (1997) Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem 272:18526–18529
Shimada H, Moewes B, Burckhardt G (1987) Indirect coupling to Na+ of p-aminohippuric acid uptake into rat renal basolateral membrane vesicles. Am J Physiol 253:F795–F801
Sweet DH, Wolff NA, Pritchard JB (1997) Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney. J Biol Chem 272:30088–30095
Uchino H, Tamai I, Yamashita K, Minemoto Y, Sai Y, Yabuuchi H, Miyamoto K, Takeda E, Tsuji A (2000) p-Aminohippuric acid transport at renal apical membrane mediated by human inorganic phosphate transporter NPT1. Biochem Biophys Res Commun 270:254–259
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF (2008) SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat Genet 40:437–442
Wright EM (1985) Transport of carboxylic acids by renal membrane vesicles. Annu Rev Physiol 47:127–141
Acknowledgments
This study was supported in part by grants from from the Japan Society for the Promotion of Science [JSPS KAKENHI 24590328 (K.H.), 23590647 (P.J.), 26461258 (N.A.)], the Strategic Research Foundation Grant-aided Project for Private Universities (S1412001), the Science Research Promotion Fund of the Japan Private School Promotion Foundation, the Gout Research Foundation of Japan, the Shimabara Science Promotion Foundation (K.H.), a Dokkyo Medical University Investigator-Initiated Research Grant (N.O., M.O.), and Research grant of Seki Minato Memorial Awards of the Seki Minato Foundation (P.J., N.A.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosure of potential conflicts of interest
There are no conflicts of interest associated with the authors who contributed to this manuscript.
Additional information
Naoyuki Otani and Motoshi Ouchi contributed equally to this work.
Rights and permissions
About this article
Cite this article
Otani, N., Ouchi, M., Hayashi, K. et al. Roles of organic anion transporters (OATs) in renal proximal tubules and their localization. Anat Sci Int 92, 200–206 (2017). https://doi.org/10.1007/s12565-016-0369-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12565-016-0369-3