Functional Analysis of Human Sodium-Phosphate Transporter 4 (NPT4/SLC17A3) Polymorphisms

Jutabha, Promsuk; Anzai, Naohiko; Kimura, Tōru; Taniguchi, Atsuo; Urano, Wako; Yamanaka, Hisashi; Endou, Hitoshi; Sakurai, Hiroyuki

doi:10.1254/jphs.10228sc

Cited by 19 publications

(13 citation statements)

References 16 publications

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“…Since reabsorptive urate by apical proximal tubule transporters may leak back into the tubule lumen via apical urate transporter NPT4, the inhibition of urate transport at NPT4 site by loop diuretics and thiazide diuretics appears consistent with the idea of diuretic-induced hyperuricemia. Our current data and the previous data illustrating 4 as a substrate of NPT4 [14,17] and OAT1/OAT3 [18] support the notion that transepithelial secretory transport of loop and thiazide diuretics in renal proximal tubule is mediated by multispecific OATs, OAT1 and OAT3 at the basolateral side, and also via the apical voltage-driven OAT NPT4. As depicted in Figure 2, these transport processes allow the diuretics to reach their site of action at the thick ascending limb of Henle's loop and distal convoluted tubule.…”

Section: Functional Properties Of Npt4 and Its Localizationsupporting

confidence: 89%

“…[17] Urate, PAH, estrone sulfate, and bumetanide transport were observed in five NPT4 variants (A100T, G239V, V257F, G279R, P378L). Compared to the wild-type clone, P378L did not show any transport function for all four substrates tested.…”

Section: Single Nucleotide Polymorphisms (Snps) On Slc17a3/npt4mentioning

confidence: 92%

“…[ 14 C]Urate, [ 3 H]estrone sulfate, and [ 3 H]bumetanide were transported into NPT4-expressed oocytes. [14,17] Therefore, urate, estrone sulfate, and bumetanide are NPT4 substrates. Thus, NPT4 operates as a multispecific transporter for anionic drugs and urate.…”

Section: Functional Properties Of Npt4 and Its Localizationmentioning

confidence: 99%

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Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule

Jutabha

Anzai

Wempe

et al. 2011

Nucleosides, Nucleotides and Nucleic Acids

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Uric acid (urate) is the end product of purine metabolism in humans. Human kidneys reabsorb a large proportion of filtered urate. This extensive renal reabsorption, together with the fact that humans do not possess uricase that catalyzes the biotransformation of urate into allantoin, results in a higher plasma urate concentration in humans compared to other mammals. A major determinant of plasma urate concentration is renal excretion as a function of the balance between reabsorption and secretion. We previously identified that renal urate absorption in proximal tubular epithelial cells occurs mainly via apical urate/anion exchanger, URAT1/SLC22A12, and by facilitated diffusion along the trans-membrane potential gradient by the basolateral voltage-driven urate efflux transporter, URATv1/SLC2A9/GLUT9. In contrast, the molecular mechanism by which renal urate secretion occurs remains elusive. Recently, we reported a newly characterized human voltage-driven drug efflux transporter, hNPT4/SLC17A3, which functions as a urate exit pathway located at the apical side of renal proximal tubules. This transporter protein has been hypothesized to play an important role with regard to net urate efflux. An in vivo role of hNPT4 is supported by the fact that missense mutations in SLC17A3 present in hyperuricemia patients with urate underexcretion abolished urate efflux capacity in vitro. Herein, we report data demonstrating that loop diuretics and thiazide diuretics substantially interact with hNPT4. These data provide molecular evidence for loop and thiazide-diuretics-induced hyperuricemia. Thus, we propose that hNPT4 is an important transepithelial proximal tubular transporter that transports diuretic drugs and operates functionally with basolateral organic anion transporters 1/3 (OAT1/OAT3).

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Section: Functional Properties Of Npt4 and Its Localizationsupporting

confidence: 89%

Section: Single Nucleotide Polymorphisms (Snps) On Slc17a3/npt4mentioning

confidence: 92%

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Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule

Jutabha

Anzai

Wempe

et al. 2011

Nucleosides, Nucleotides and Nucleic Acids

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“…NPT1 and NPT4 localize to the apical membrane of RPTECs and are hypothesized to export urate into the tubule lumen as part of the urate secretory pathway. Support for this functional role comes from the identification and analysis of missense mutations involved in hyperuricemia and/or gout that exhibit altered urate transport activities [35,[44][45][46][47]. Moreover, it has been suggested that hyperuricemia induced by diuretics may be due to inhibition of NPT4 [45].…”

Section: Npt1 Npt4 and Npt5mentioning

confidence: 99%

Uric acid transporter inhibitors for gout

Tan¹,

Miner²

2017

ADMET DMPK

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Gout is a common inflammatory arthritis that is caused by chronically-elevated serum uric acid (sUA) levels (hyperuricemia). KeywordsGout; hyperuricemia; uricase; URAT1; coevolution; urate transporters for urate homeostasis Overview Gout and hyperuricemiaGout is a debilitating inflammatory arthritis of increasing prevalence that is caused by chronically elevated levels of serum uric acid (sUA), or hyperuricemia, defined as concentrations exceeding 6.8 mg/dL (408 μM). In healthy nongouty individuals, serum urate levels are normally in the range of 3.5-7 mg/dL (210 -420 μM) [1]. Prolonged hyperuricemia can initiate the precipitation of the uric acid in joints and other tissues, and these deposits can trigger an acute and painful immune response known as a gout flare. Hyperuricemia is also strongly and independently associated with a number of other important disorders including hypertension, cardiovascular disease and metabolic syndrome [2]. A number of therapies for gout that lower sUA levels target transporters for uric acid, some which are also important drug transporters. Uric acid homeostasis in humans in health and diseaseUric acid is produced mainly in the liver and gastrointestinal tract by the degradation of endogenous and dietary purines. Sources of endogenous purines include nucleotides such as ATP, and DNA and RNA that are recovered from dying cells. These purines are degraded into uric acid by xanthine oxidase in the liver. Dietary purines are absorbed in the gut by the CNT2 transporter and are quantitatively metabolized to uric acid by endogenous xanthine oxidase within intestinal enterocytes (see Figure 1b). In non-primate mammals, uric acid is converted to more highly soluble allantoin by urate oxidase (uricase). In primates including humans, however, uric acid is the end product of purine catabolism due to the progressive

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“…cRNA synthesis and uptake measurements were performed as previously described (14). Briefly, the cDNA was linearized with Xba I, and the cDNA insert transcribed in vitro with the T7 mMESSAGE mMACHINE cRNA synthesis kit (Ambion, Austin, TX, USA).…”

mentioning

confidence: 99%

A Novel Human Organic Anion Transporter NPT4 Mediates the Transport of Ochratoxin A

et al. 2011

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Abstract. In the present study, we investigated the transport of nephrotoxic mycotoxin ochratoxin A (OTxA) by a novel human organic anion transporter hNPT4 using the Xenopus oocyte expression system. hNPT4 mediated time-and concentration-dependent uptake of OTxA (K m : 802.8 μM) in a pH-and voltage-sensitive manner. Cis-inhibition experiments suggest that the substrate selectivity of hNPT4 is similar to that of hOAT4. The fact that the K m of OTxA for the efflux transporter hNPT4 was much higher than those for the uptake transporters hOAT1 and hOAT3 may favor the accumulation of OTxA in the tubular cell and lead to nephrotoxicity.

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Functional Analysis of Human Sodium-Phosphate Transporter 4 (NPT4/SLC17A3) Polymorphisms

Abstract: Abstract. We analyzed the functional properties of five nonsynonymous single nucleotide polymorphisms (SNPs) in the sodium-phosphate transporter NPT4 gene (SLC17A3) using the Xenopus oocyte expression system. NPT4 variants carrying SNP V257F, G279R, or P378L exhibited reduced transport of

Cited by 19 publications

References 16 publications

Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule

Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule

Uric acid transporter inhibitors for gout

A Novel Human Organic Anion Transporter NPT4 Mediates the Transport of Ochratoxin A

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