SLC2A9 Is a High-Capacity Urate Transporter in Humans

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dc.contributor.authorCaulfield, Mark J.
dc.contributor.authorMunroe, Patricia B.
dc.contributor.authorO'Neill, Deb
dc.contributor.authorWitkowska, Kate
dc.contributor.authorCharchar, Fadi J.
dc.contributor.authorDoblado, Manuel
dc.contributor.authorEvans, Sarah
dc.contributor.authorEyheramendy, Susana
dc.contributor.authorOnipinla, Abiodun
dc.contributor.authorHoward, Philip
dc.contributor.authorShaw Hawkins, Sue
dc.contributor.authorDobson, Richard J.
dc.contributor.authorWallace, Chris
dc.contributor.authorNewhouse, Stephen J.
dc.contributor.authorBrown, Morris
dc.contributor.authorConnell, John M.
dc.contributor.authorDominiczak, Anna
dc.contributor.authorFarrall, Martin
dc.contributor.authorLathrop, G. Mark
dc.contributor.authorSamani, Nilesh J.
dc.contributor.authorKumari, Meena
dc.contributor.authorMarmot, Michael
dc.contributor.authorBrunner, Eric
dc.contributor.authorChambers, John
dc.contributor.authorElliott, Paul
dc.contributor.authorKooner, Jaspal
dc.contributor.authorLaan, Maris
dc.contributor.authorOrg, Elin
dc.contributor.authorVeldre, Gudrun
dc.contributor.authorViigimaa, Margus
dc.contributor.authorCappuccio, Francesco P.
dc.contributor.authorJi, Chen
dc.contributor.authorIacone, Roberto
dc.contributor.authorStrazzullo, Pasquale
dc.contributor.authorMoley, Kelle H.
dc.contributor.authorCheeseman, Chris
dc.date.accessioned2024-01-10T12:42:42Z
dc.date.available2024-01-10T12:42:42Z
dc.date.issued2008
dc.description.abstractBackground
dc.description.abstractSerum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.
dc.description.abstractMethods and Findings
dc.description.abstractWe expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200-500 mu M). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (K-i = 27 mu M). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case-control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size -0.12 mm Hg, 95% CI -0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size -0.03 mm Hg, 95% CI -0.39 to 0.31, p = 0.82).
dc.description.abstractConclusions
dc.description.abstractThis study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.
dc.description.funderMedical Research Council (MRC) of Great Britain
dc.description.funderBritish Heart Foundation
dc.description.funderNational Institutes of Health (NIH)
dc.description.funderCanadian Breast Cancer Foundation
dc.description.funderWellcome Trust
dc.description.funderThe London Genome Centre
dc.description.funderBritish Heart Foundation
dc.description.funderWellcome Trust International Senior Research Fellowship
dc.description.funderBiomedical Science in Central Europe
dc.description.funderEstonian Ministry of Education and Science
dc.description.funderMRC Research Professorship
dc.description.funderMRC
dc.description.funderEconomic and Social Research Council
dc.description.funderHealth and Safety Executive
dc.description.funderDepartment of Health
dc.description.funderNational Heart Lung and Blood Institute
dc.description.funderNIH
dc.description.funderNational Institute on Aging (NIA)
dc.description.funderNIH, Agency for Health Care Policy Research
dc.description.funderNIA
dc.description.funderBritish Heart Foundation
dc.description.funderMedical Research Council
dc.description.funderEUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
dc.description.funderEUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT
dc.description.funderNATIONAL HEART, LUNG, AND BLOOD INSTITUTE
dc.description.funderNATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
dc.description.funderNATIONAL INSTITUTE ON AGING
dc.format.extent15 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1371/journal.pmed.0050197
dc.identifier.eissn1549-1676
dc.identifier.issn1549-1277
dc.identifier.pubmedidMEDLINE:18842065
dc.identifier.urihttps://doi.org/10.1371/journal.pmed.0050197
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/77534
dc.identifier.wosidWOS:000260424100015
dc.information.autorucMatemática;Eyheramendy S;S/I;82611
dc.issue.numero10
dc.language.isoen
dc.nota.accesoSin adjunto
dc.pagina.final1523
dc.pagina.inicio1509
dc.publisherPUBLIC LIBRARY SCIENCE
dc.revistaPLOS MEDICINE
dc.rightsregistro bibliográfico
dc.subjectSERUM URIC-ACID
dc.subjectGLUCOSE TRANSPORTERS
dc.subjectMETABOLIC SYNDROME
dc.subjectPROXIMAL TUBULE
dc.subjectGLUT9
dc.subjectHYPERTENSION
dc.subjectKIDNEY
dc.subjectEXPRESSION
dc.subjectIDENTIFICATION
dc.subjectHYPERURICEMIA
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleSLC2A9 Is a High-Capacity Urate Transporter in Humans
dc.typeartículo
dc.volumen5
sipa.codpersvinculados82611
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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