Increased Expression of<i>SLC2A9</i>Decreases Urate Excretion From the Kidney

Kimura, Tōru; Amonpatumrat, Sirirat; Tsukada, Ai; Fukutomi, Toshiyuki; Jutabha, Promsuk; Thammapratip, Thanapol; Lee, Mi Kyung; Ichida, Kimiyoshi; Anzai, Naohiko; Sakurai, Hiroyuki

doi:10.1080/15257770.2011.628354

Cited by 15 publications

(12 citation statements)

References 8 publications

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“…The phenotypic analysis of mice with targeted deletion of Slc2a9 is complicated by the widespread expression pattern of this gene because the entry of urate via the Glut9 protein at the basolateral membrane of murine hepatocytes facilitates uricase-catalyzed metabolism to allantoin (98). Transgenic mice with overexpression of Glut9 in the proximal tubule, driven by the URAT1 promoter, develop mild hyperuricemia that is not statistically significant from that of littermates, likely due to the mitigating effect of murine uricase on hyperuricemia; however, urinary urate excretion is reduced in these mice (117), indicating a potential renal mechanism for the effect of GLUT9 activation in human hyperuricemia and gout.…”

Section: The Glut9 Urate Transportermentioning

confidence: 88%

The Molecular Physiology of Uric Acid Homeostasis

Mandal

Mount²

2015

Annu. Rev. Physiol.

426

331

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Uric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia.

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Section: The Glut9 Urate Transportermentioning

confidence: 88%

The Molecular Physiology of Uric Acid Homeostasis

Mandal

Mount²

2015

Annu. Rev. Physiol.

426

331

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“…Another urate reabsorptive transporter, SLC22A12/URAT1, is known to be expressed at the apical membrane of the proximal tubular cells [15]. Thus, we proposed that urate is reabsorbed via SLC22A12 from the urinary space into the kidney proximal tubular cell and then out of the cell to the interstitial space via SLC2A9 [16]. Based on the differential trafficking of 2 splice variants in the polarized epithelial cell, it is likely that SLC2A9 expressed in the basolateral membrane of the kidney proximal tubule is the longer isoform.…”

Section: Introductionmentioning

confidence: 99%

Expression of SLC2A9 Isoforms in the Kidney and Their Localization in Polarized Epithelial Cells

et al. 2014

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BackgroundMany genome-wide association studies pointed out that SLC2A9 gene, which encodes a voltage-driven urate transporter, SLC2A9/GLUT9 (a.k.a. URATv1), as one of the most influential genes for serum urate levels. SLC2A9 is reported to encode two splice variants: SLC2A9-S (512 amino acids) and SLC2A9-L (540 amino acids), only difference being at their N-termini. We investigated isoform-specific localization of SLC2A9 in the human kidney and role of N-terminal amino acids in differential sorting in vitro.Methodology/Principal FindingsIsoform specific antibodies against SLC2A9 were developed and human kidney sections were stained. SLC2A9-S was expressed in the apical side of the collecting duct while SLC2A9-L was expressed in the basolateral side of the proximal tubule. GFP fused SLC2A9s were expressed in MDCK cells and intracellular localization was observed. SLC2A9-S was expressed at both apical and basolateral membranes, whereas SLC2A9-L was expressed only at the basolateral membrane. Although SLC2A9-L has a putative di-leucine motif at 33th and 34th leucine, deletion of the motif or replacement of leucine did not affect its subcellular localization. When up to 16 amino acids were removed from the N-terminal of SLC2A9-S or when up to 25 amino acids were removed from the N-terminal of SLC2A9-L, there was no change in their sorting. Deletion of 20 amino acids from SLC2A9-S was not expressed in the cell. More than 30 amino acids deletion from SLC2A9-L resulted in expression at both apical and basolateral membranes as well as in the lysosome. When amino acids from 25th and 30th were changed to alanine in SLC2A9-L, expression pattern was the same as wild-type.Conclusions/SignificanceSLC2A9-L was expressed in the basolateral membrane of kidney proximal tubules in humans and this isoform is likely to responsible for urate reabsorption. N-terminal amino acids unique to each isoform played an important role in protein stability and trafficking.

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“…7) The altered expressions of the urate transporters are suggested to be associated with hyperuricemia. 8,9) Moreover, PDZ domain-containing protein 1 (PDZK1), 10) a scaffolding protein, has been identified to participate in the process of urate transport in kidney.…”

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confidence: 99%

Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

Yang

Gao

Niu

et al. 2015

Biological & Pharmaceutical Bulletin

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Mangiferin, a natural glucosyl xanthone from the leaves of Mangifera indica L., was previously shown to exert potent hypouricemic effects associated with inhibition of the activity of xanthine dehydrogenase/ oxidase. The present study aimed to evaluate its uricosuric effect and possible molecular mechanisms underlying the renal urate transporters responsible for urate reabsorption in vivo. Mangiferin (1.5-24.0 mg/kg) was administered intragastrically to hyperuricemic mice and rats induced by the intraperitoneal injection of uric acid and potassium oxonate, respectively. The uricosuric effect was evaluated by determining the serum and urinary urate levels as well as fractional excretion of uric acid (FEUA). The mRNA and protein levels of renal urate-anion transporter 1 (URAT1), organic anion transporter 10 (OAT10), glucose transporter 9 (GLUT9), and PDZ domain-containing protein (PDZK1) were analyzed. The administration of mangiferin significantly decreased the serum urate levels in hyperuricemic mice in a dose-and time-dependent manner. In hyperuricemic rats, mangiferin also reduced the serum urate levels and increased the urinary urate levels and FEUA. These results indicate that mangiferin has uricosuric effects. Further examination showed that mangiferin markedly inhibited the mRNA and protein expression of renal URAT1, OAT10, and GLUT9 in hyperuricemic rats, but did not interfere with PDZK1 expression. Taken together, these findings suggest that mangiferin promotes urate excretion by the kidney, which may be related to the inhibition of urate reabsorption via downregulation of renal urate transporters.

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Increased Expression ofSLC2A9Decreases Urate Excretion From the Kidney

Cited by 15 publications

References 8 publications

The Molecular Physiology of Uric Acid Homeostasis

The Molecular Physiology of Uric Acid Homeostasis

Expression of SLC2A9 Isoforms in the Kidney and Their Localization in Polarized Epithelial Cells

Mangiferin Inhibits Renal Urate Reabsorption by Modulating Urate Transporters in Experimental Hyperuricemia

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