URAT1

URAT1 (urate transporter 1)

Aliases: OAT4L, RST
Gene name:  Solute carrier family 22 member 12 (SLC22A12)

Summary

URAT1, a member of the OAT (organic anion transporter) family, is an anion-exchanging uptake transporter localized to the apical (brush border) membrane of renal proximal tubular cells [1, 2], where it mediates the re-absorption of uric acid from the proximal tubule, thereby playing a key role in uric acid homeostasis [3-5]. Circulating uric acid is thought to protect against bone mineral density loss and oxidative damage; on the other hand, excess serum uric acid results in gout, hypertension, and cardiovascular disease. URAT1 appears to have a limited substrate specificity, and no drug substrates of URAT1 are known.  However, probenecid and benzbromarone are clinically used as uricosuric agents, as they inhibit URAT1 and other renal OATs.  Other clinical inhibitors have also been identified, although their clinical effects are often considered a relatively benign side effect.  Impaired URAT1 activity, due to functional polymorphisms can result in hyper- or hypouricemia.  
As knowledge grows of both the mechanisms involved in uric acid homeostasis and the beneficial impacts of serum uric acid, URAT1 may become a relevant transporter for DDI or safety evaluations, but currently there is insufficient information to include this transporter in FDA or EMA regulatory guidances for the evaluation of drug interactions or safety liabilities.

Localization

URAT1 has 12 predicted transmembrane domains and is predominantly expressed in the cytoplasm and luminal cell membrane of proximal tubule cells in fetal and adult kidney cortex [1].  URAT1 is also expressed (albeit at lower levels) in the cytoplasm of striated ductal cells in the salivary gland [2] and in vascular smooth muscle cells [6]. In the salivary glands, URAT1 is distributed along the entire surface, including the ductal and acinar cells, suggesting a role in the transport of organic acids and uric acid in the whole salivary gland [2].

Function, physiology, and clinically significant polymorphisms

URAT1 belongs to the OAT transporter family.  It is an anion exchanger that specifically reabsorbs uric acid from the proximal tubule in exchange for monovalent anions such as lactate, nicotinoate, acetoacetate, and hydroxybutyrate. Uric acid reabsorption from the tubule is electroneutral and can be trans-stimulated by the Cl– gradient, or the lactate gradient generated by the sodium-monocarboxylate transporter [1, 7].  
Uric acid handling by the kidney is complex, and is an active area of research.  In simple terms, uric acid is firstly eliminated into the proximal tubule by glomerular filtration and/or by the active uptake via OAT1 and 3; next, it is eliminated from the proximal cell by the urate channel (possibly SLC17A3); then it is reabsorbed from the proximal tubule into the cell by URAT1 (and possibly OAT4).  Reabsorbed uric acid is then returned to the blood via another transporter, GLUT9 (SLC2A9).  
The precise physiological role of uric acid is only beginning to be appreciated. Given its role in the development of gout, hypertension, and cardiovascular disease, it has traditionally been regarded as detrimental to human health, but this is in contradiction to the naturally high levels of circulating uric acid maintained in humans (far higher than in other species).  Current research indicates an antioxidant role, which may be important in the development of multiple sclerosis, in metabolic stress in muscle tissue, or even in inflammatory response [8-10]. Hyperuricemia seems to protect against low bone mineral density, osteoporosis, and fractures [11], and due to its antioxidant effects uric acid may retard age-related cognitive decline [12].
Two transcript variants encoding different isoforms have been reported for SLC22A12. Single nucleotide polymorphisms of URAT1 are associated with altered (increased or decreased) reabsorption of uric acid by the kidneys in different human populations [13, 14]. These altered rates of reabsorption result in hyperuricemia and hypouricemia, respectively.  Three different mutations of URAT1, found in patients with idiopathic renal hypouricemia, express proteins that do not support urate transport, consistent with a central role of URAT1 in renal urate reabsorption. The first characterized mutation that was shown to result in familial idiopathic hypouricemia was a missense mutation leading to a premature stop codon (W258X) [1].  Idiopathic renal hypouricemia in patients of different ethnicities (from Japan, Korea, China, Macedonia, Britain, and USA) has been linked to polymorphisms in SLS22A12.  The W258X variant of URAT1 is a typical mutation found in Japanese and Korean populations [15, 16].  The allele frequency of W258X in the general population in Japan was found to be 1.9% [17].  Macedonian and British patients with hypouricemia with renal stone disease and hematuria were found to have missense mutations in SLC22A12 [18].  A genome-wide association study conducted with 6890 African Americans and 21708 Europeans associated URAT1 G65W with reduced activity [19] and showed that a single heterozygous change in URAT1 may be significant. This variant allele provided a protective effect against gout, but could also be an at-risk allele for the hypouricemia [19].
HNF-1α is thought to regulate the expression of human URAT1 [14].

Clinical significance

Hyperuricemia (i.e. chronically elevated serum uric acid levels due to reduced excretion of uric acid) is associated with the development of gout, hypertension, and cardiovascular diseases. Uricosuric drugs such as benzbromarone and probenecid are clinical inhibitors of URAT1, increasing renal excretion of uric acid, and thereby reducing serum levels [20].  Lesinurad, an oral inhibitor of URAT1 for the treatment of hyperuricaemia associated with gout, was approved by the FDA in 2015 [21]. The angiotensin receptor blockers losartan and fenofibric acid also inhibit URAT1 (demonstrated in vitro), and reduce serum concentrations of urate in hypertensive patients [22].  The URAT1 rs3825016 and rs1529909 polymorphisms were shown to influence the uricosuric action of losartan [23]. Salicylate and benzylpenicillin also interact with URAT1 and affect urinary uric acid excretion [24]. However, most clinical inhibitors of URAT1 are also well-known inhibitors of other renal OAT family members, which also transport uric acid.  Therefore, the picture is a somewhat complex one. Thus far, there are no known drug substrates of URAT1.     
Salivary uric acid levels are higher than blood levels in patients on benzbromarone, and this may be due to expression of URAT1 and other OATs in this tissue.  The clinical consequences of this finding are unknown [2].

Regulatory requirements

Currently, no drug substrates of URAT1 have been found, and a number of uricosuric drugs that inhibit URAT1 are in clinical use. Some drugs have unintended uricosuric side effects; however, these are generally considered benign. As knowledge grows of both the mechanisms involved in uric acid homeostasis and the beneficial impacts of serum uric acid, URAT1 may become a relevant transporter for DDI or safety evaluations, but currently there is insufficient information to include this transporter in regulatory guidances for the evaluation of drug interactions or safety liabilities.

References

1.    Enomoto, A., et al., Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature, 2002. 417(6887): p. 447-52.
2.    Ikarashi, R., K. Shibasaki, and A. Yamaguchi, Immunohistochemical studies of organic anion transporters and urate transporter 1 expression in human salivary gland. Acta Odontologica Scandinavica, 2012.
3.    Wallace, C., et al., Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet, 2008. 82(1): p. 139-49.
4.    Vitart, V., et al., SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nature Genetics, 2008. 40(4): p. 437-42.
5.    Wright, A.F., et al., A 'complexity' of urate transporters. Kidney International, 2010. 78(5): p. 446-52.
6.    Price, K.L., et al., Human vascular smooth muscle cells express a urate transporter. Journal of the American Society of Nephrology, 2006. 17(7): p. 1791-5.
7.    Hagenbuch, B., Drug uptake systems in liver and kidney: a historic perspective. Clinical Pharmacology and Therapeutics, 2010. 87(1): p. 39-47.
8.    Hediger, M.A., et al., Molecular physiology of urate transport. Physiology (Bethesda), 2005. 20: p. 125-33.
9.    Mount, D.B., Molecular physiology and the four-component model of renal urate transport. Current Opinion in Nephrology and Hypertension, 2005. 14(5): p. 460-3.
10.    Enomoto, A. and H. Endou, Roles of organic anion transporters (OATs) and a urate transporter (URAT1) in the pathophysiology of human disease. Clin Exp Nephrol, 2005. 9(3): p. 195-205.
11.    Veronese, N., et al., Hyperuricemia protects against low bone mineral density, osteoporosis and fractures: a systematic review and meta-analysis. Eur J Clin Invest, 2016. 46(11): p. 920-930.
12.    Tuven, B., et al., Uric acid may be protective against cognitive impairment in older adults, but only in those without cardiovascular risk factors. Exp Gerontol, 2017. 89: p. 15-19.
13.    Graessler, J., et al., Association of the human urate transporter 1 with reduced renal uric acid excretion and hyperuricemia in a German Caucasian population. Arthritis and Rheumatism, 2006. 54(1): p. 292-300.
14.    Wakida, N., et al., Mutations in human urate transporter 1 gene in presecretory reabsorption defect type of familial renal hypouricemia. Journal of Clinical Endocrinology and Metabolism, 2005. 90(4): p. 2169-74.
15.    Cheong, H.I., et al., Mutational analysis of idiopathic renal hypouricemia in Korea. Pediatric Nephrology, 2005. 20(7): p. 886-90.
16.    Mima, A., et al., Acute renal failure after exercise in a Japanese sumo wrestler with renal hypouricemia. American Journal of the Medical Sciences, 2008. 336(6): p. 512-4.
17.    Kuriki, S., et al., SLC22A12 W258X frequency according to serum uric acid level among Japanese health checkup examinees. Nagoya Journal of Medical Science, 2011. 73(1-2): p. 41-8.
18.    Tasic, V., et al., Clinical and functional characterization of URAT1 variants. PLoS One, 2011. 6(12): p. e28641.
19.    Tin, A., et al., Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele. Human Molecular Genetics, 2011. 20(20): p. 4056-68.
20.    Iwanaga, T., et al., Involvement of uric acid transporter in increased renal clearance of the xanthine oxidase inhibitor oxypurinol induced by a uricosuric agent, benzbromarone. Drug Metab Dispos, 2005. 33(12): p. 1791-5.
21.    Hoy, S.M., Lesinurad: First Global Approval. Drugs, 2016. 76(4): p. 509-16.
22.    Hamada, T., et al., Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients. American Journal of Hypertension, 2008. 21(10): p. 1157-62.
23.    Sun, H., et al., URAT1 gene polymorphisms influence uricosuric action of losartan in hypertensive patients with hyperuricemia. Pharmacogenomics, 2015. 16(8): p. 855-63.
24.    Shin, H.J., et al., Interactions of urate transporter URAT1 in human kidney with uricosuric drugs. Nephrology (Carlton), 2011. 16(2): p. 156-62.