Involvement of Uric Acid Transporters in Alteration of Serum Uric Acid Level by Angiotensin II Receptor Blockers

One of the characteristics of chronic kidney disease (CKD) is the accumulation of uremic solutes in the plasma. Less is known about the effects of uremic solutes on transporters that may play critical roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes were identified as inhibitors of OAT1 and OAT3, respectively. Several of them inhibited OAT1 or OAT3 at clinically relevant concentrations and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most drugs that are known substrates of OAT1/3 deteriorated faster than the renal filtration in CKD. Collectively, these data suggest that through inhibition of OAT1 and OAT3, uremic solutes contribute to the decline in renal drug clearance in patients with CKD.

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“…4 Recent data suggest free water-soluble solutes could also interact with OAT1/3. 35,36 4.1. Uremic Solutes Screening.…”

Section: Discussionmentioning

confidence: 99%

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

et al. 2016

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“…3,30) Many SLC22A family members, including URAT1, OAT1, OAT3, OAT4 and OAT10, are known to transport uric acid and to be involved in uric acid handling in kidney. 8,11,25,26,31,32) So far, it has been unclear whether OAT2 expressed at the basolateral membrane of proximal tubular cells is involved in uric acid transport. Our present data represent the first evidence that OAT2 can transport uric acid.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, several angiotensin receptor blockers (ARBs) and diuretics hydrochlorothiazide and furosemide were similarly tested for their inhibitory effects on OAT2-mediated transport of uric acid, since these drugs have been reported to alter SUA levels. [6][7][8]27,28) Losartan (10 mM), telmisartan (10 mM), hydrochlorothiazide (100 mM) and furosemide (100 mM) significantly reduced OAT2-mediated uptake of uric acid ( Fig. 6b) to 85, 58, 65 and 18% of the control, respectively.…”

Section: Effects Of Drugs On Uric Acid Transport By Oat2mentioning

confidence: 96%

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Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human

Sato

Mamada

Anzai

et al. 2010

Biological & Pharmaceutical Bulletin

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The physiological function of organic anion transporter OAT2 (SLC22A7) remains unclear, but since OAT2 transports purine derivatives, it may be involved in renal handling of uric acid, the final metabolite of purine derivatives. In the present study, we studied uric acid transport in stably OAT2-expressing HEK293 cells (HEK293/OAT2). OAT2 mediated uptake, but not efflux, of [ ]uric acid uptake was inhibited by several mono-or dicarboxylic acids, but it was not trans-stimulated by any of the compounds tested. The pattern of inhibition of OAT2-mediated uric acid transport by various drugs was different from that of OAT1-or OAT3-mediated transport. Furthermore, OAT2-mediated transport of uric acid was inhibited by an antiuricosuric drug, pyrazinecarboxylic acid. These results revealed distinct characteristics of uric acid transport via OAT2 compared with other uric acid transporters, suggesting that OAT2 plays a role in renal uric acid uptake from blood as a first step of tubular secretion. OAT2 may therefore be a potential target for regulating serum uric acid level.

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“…OAT1 (SLC22A6) and OAT3 (SLC22A8) are expressed at the basolateral membrane and facilitate urate uptake from the circulation into tubular cells (17,31,38). Cellular elimination of urate at the apical membrane is mediated by voltage-driven Na ϩ -P i cotransporter (NPT)1 (SLC17A1) and NPT4 (SLC17A3), and the ATP-dependent transporter ABCG2 and ABCC4 (18,19,46,51).…”

mentioning

confidence: 99%

Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α

Prestin

Wolf

Strohbach

et al. 2014

American Journal of Physiology-Renal Physiology

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handling of urate is realized by a network of uptake and efflux transporters, including members of drug transporter families such as solute carrier proteins and ATP-binding cassette transporters. Solute carrier family 2, member 9 (SLC2A9), is one key factor of this so called "urate transportosome." The aim of the present study was to understand the transcriptional regulation of SLC2A9 and to test whether identified factors might contribute to a coordinated transcriptional regulation of the transporters involved in urate handling. In silico analysis and cell-based reporter gene assays identified a hepatocyte nuclear factor (HNF)4␣-binding site in the promoter of SLC2A9 isoform 1, whose activity was enhanced by transient HNF4␣ overexpression, whereas mutation of the binding site diminished activation. HNF4␣ overexpression induced endogenous SLC2A9 expression in vitro. The in vivo role of HNF4␣ in the modulation of renal SLC2A9 gene expression was supported by findings of quantitative real-time RT-PCR analyses and chromatin immunoprecipitation assays. Indeed, mRNA expression of SLC2A9 and HNF4␣ in human kidney samples was significantly correlated. We also showed that in renal clear cell carcinoma, downregulation of HNF4␣ mRNA and protein expression was associated with a significant decline in expression of the transporter. Taken together, our data suggest that nuclear receptor family member HNF4␣ contributes to the transcriptional regulation of SLC2A9 isoform 1. Since HNF4␣ has previously been assumed to be a modulator of several urate transporters, our findings support the notion that there could be a transcriptional network providing synchronized regulation of the functional network of the urate transportosome.

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Involvement of Uric Acid Transporters in Alteration of Serum Uric Acid Level by Angiotensin II Receptor Blockers

Abstract: Valsartan, olmesartan, and pratosartan could inhibit the OAT3-mediated uric acid secretion in clinical situations. Furthermore losartan could inhibit ATP-dependent uric acid secretion by MRP4. These effects may explain partially the alteration of serum uric acid level by ARBs.

Cited by 81 publications

References 23 publications

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3

Renal Secretion of Uric Acid by Organic Anion Transporter 2 (OAT2/SLC22A7) in Human

Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α

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