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. 2018 May 31;5:160. doi: 10.3389/fmed.2018.00160

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Copyright © 2018 Benn, Dua, Gurrell, Loudon, Pike, Storer and Vangjeli.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Role of transporters in the renal proximal tubule on urate handling. Within an individual nephron in the kidney (yellow), filtration of water and solutes occurs in the glomerular capsule from the afferent arteriole into the renal tubule (pink shading). Tubular reabsorption (green shading) is predominantly mediated by the proximal convoluted tubule whereas tubular secretion extracts uric acid (and other substances) from peritubular capillaries (purple shading) and secretes them into the tubular fluid for urinary excretion. Urate transporters in renal proximal tubule epithelial cells actively mediate the secretion and reabsorption of urate. The balance between these processes determines the net excretion levels from the kidney. The anion transporters SLC22A6 (OAT1) and SLC22A8 (OAT3) localized on the basolateral membranes transport urate from the interstitial space in the blood depending on the gradients for exchanged anions but have not been shown to exhibit a genetic linkage with hyperuricemia or gout risk (gray box). On the apical membrane, ABCG2, SLC17A1 (NPT1), SLC17A3 (NPT4), ABCC4 (MRP4), UAT (Galectin 9) have all been shown to contribute to the secretory transport of urate into the tubule lumen and leading to urinary excretion; a number of these have been genetically associated with hyperuricemia and gout risk (green boxes). Exchange gradients upstream of urate anion exchange are enabled through the actions of SLC13A3 (NaD3), SLC5A8 (SCMT1), and SLC5A12 (SCMT2). In renal reabsorption, the apical urate-anion exchanger SLC22A12 (URAT1) has been shown to play a predominant role in urate homeostasis and indeed several variants have been identified to be associated with gout and hyperuricemia risk (green box). Additional contributions to urate reabsorption are mediated by SLC22A11 (OAT4) and SLC22A11 (OAT10) (gray boxes, not genetically associated with gout/hyperuricemia risk) and the short isoform of SLC2A9v2 (GLUT9, green box) on the apical membrane. The long isoform of SLC2A9v1 (GLUT9, green box) is the only known transporter to mediate basolateral efflux of urate back into circulation; which is in accordance with its genetic association for gout and hyperuricemia risk in addition to rare mutations associated with hypouricemia.