Renal Transport of Organic Compounds Mediated by Mouse Organic Anion Transporter 3 (Moat3): Further Substrate Specificity of Moat3

Kobayashi, Yasuna; Ohshiro, Naomi; Tsuchiya, Ayumi; Kohyama, Noriko; Ohbayashi, Masayuki; Yamamoto, Toshinori

doi:10.1124/dmd.32.5.479

Cited by 41 publications

(27 citation statements)

References 33 publications

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“…Northern blotting revealed that mOat1 mRNA is expressed abundantly in kidney, weakly in brain, and not at all in heart, placenta, lung, liver, spleen, and stomach (14,23). Similar tissue distribution was shown for mOat3 mRNA, which is highly expressed in kidney, weakly in brain and eyes, and not detected in liver, heart, spleen, lung, skeletal muscle, testis, and pancreas (4,21,29,36). The RT-PCR studies detected mOat3 mRNA in the choroid plexus and capillary endothelial cells of the mouse brain (29,36).…”

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confidence: 55%

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Breljak

Brzica

Sweet

et al. 2013

American Journal of Physiology-Renal Physiology

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Breljak D, Brzica H, Sweet DH, Anzai N, Sabolic I. Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys. Am J Physiol Renal Physiol 304: F1114 -F1126, 2013. First published February 6, 2013 doi:10.1152/ajprenal.00201.2012.-In the mouse kidney, organic anion transporter 3 (mOat3, Slc22a8) was previously localized to the basolateral membrane (BLM) of proximal tubule (PT), thick ascending limb of Henle, macula densa, distal tubule, and cortical collecting duct. However, the specificity of antiOat3 antibodies (Oat3-Ab) used in these studies was not properly verified. Moreover, the sex-dependent expression of mOat3, and of the functionally similar transporter mOat1 (Slc22a6), in the mouse kidney has been studied at mRNA level, whereas their protein expression is poorly documented. Here we investigated 1) specificity of Oat3-Abs by using Oat3 knockout (KO) mice, 2) cell localization of renal mOat3 with a specific mOat3-Ab, 3) sex-dependent expression of renal mOat3 and mOat1 proteins, and 4) hormone(s) responsible for observed sex differences. As previously shown, an Oat3-Ab against the rat protein stained the BLM of various nephron segments in wild-type (WT) mice, but the same staining pattern was noted along the nephron of Oat3 KO mice. However, the mOat3-Ab exclusively stained the BLM of PT in WT mice, where it colocalized with the mOat1 protein, whereas no staining of Oat3 protein was noted in the kidney of Oat3 KO mice. The expression of mOat3 protein was lower in male mice, upregulated by castration, and downregulated by testosterone treatment. The expression of mOat1 protein was stronger in males, downregulated by castration, and upregulated by testosterone treatment. Thus, at the protein level, mOat3 and mOat1 exhibit sex-dependent expression with an opposite pattern; mOat3 is female dominant due to androgen inhibition, while mOat1 is male dominant due to androgen stimulation. gender differences; immunocytochemistry; mouse nephron; organic anion transporters; proximal tubule; sex differences; sexual dimorphism; Oat3 knockout IN THE MAMMALIAN KIDNEY, various endogenous and exogenous organic anions (OA), such as anionic metabolites, therapeutic drugs, and environmental toxins, are eliminated by several OA transporters that operate as exchangers and belong to the large family of solute carriers 22 (OAT/SLC22 in humans; Oat/ Slc22 in animals). In proximal tubule epithelial cells, transport of OA from blood to urine is mediated by two distinct types of OATs/Oats; those localized in the basolateral membrane (BLM) mediate the cellular uptake of OA from blood, whereas those localized in the brush border membrane (BBM) mediate the exit of OA into the tubular lumen. In humans and rodents (such as mice and rats), two major BLM transporters responsible for the first step in the renal elimination of a broad range of OA are OAT1/Oat1 (SLC22A6/Slc22a6) and OAT3/Oat3 (SLC22A8/Slc22a8; Refs.

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confidence: 55%

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Breljak

Brzica

Sweet

et al. 2013

American Journal of Physiology-Renal Physiology

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“…Both transporters show broad substrate specificities. Of note, Oatp1a4 preferably mediates the uptake of amphipathic organic anions and cardiac glycosides, whereas Oat3 mediates that of both hydrophilic and amphipathic ones (Sweet et al, 2002;van Montfoort et al, 2002;Kobayashi et al, 2004;Ohtsuki et al, 2004;Ose et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Miyajima

Kusuhara²,

Fujishima³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The present study investigated the efflux transport systems of organic anions across the blood-brain barrier (BBB) using dehydroepiandrosterone sulfate (DHEAS) as a probe. The elimination of DHEAS from the brain after microinjection into the cerebral cortex was characterized in wild-type mice and mice with deficiency of well characterized organic anion transporters, organic aniontransporting polypeptide 1a4 (Oatp1a4)/Slco1a4 and organic anion transporter 3 (Oat3)/Slc22a8, at the BBB. The saturable efflux of DHEAS from the brain was completely inhibited by probenecid, benzylpenicillin, and estrone-3-sulfate and moderately inhibited by taurocholate and p-aminohippurate (50-57%). Uptake of DHEAS and estrone-3-sulfate was greater in murine Oat3 cRNA-injected oocytes than that in water-injected oocytes. Efflux of these compounds from the brain was significantly delayed in Oat3(؊/؊) mice compared with that in wild-type mice, indicating that indeed Oat3 is functionally important in vivo. Furthermore, probenecid and taurocholate inhibited DHEAS efflux completely in Oat3(؊/؊) mice. Contrary to the past report in rats that suggested involvement of Oatp1a4, specific uptake of DHEAS and estrone-3-sulfate by murine Oatp1a4 was not detected in vitro, and efflux of both compounds from the brain was not altered in Oatp1a4(؊/؊) mice. There was no significant difference in the uptake of DHEAS by brain slices prepared from wild-type, Oatp1a4(؊/؊), and Oat3(؊/؊) mice. Taken together, these results suggest that Oat3 plays a significant role in the efflux of steroid conjugates across the BBB in mice and that the BBB also expresses other unknown organic anion transporters for the efflux of DHEAS. Transport mechanisms of organic anions at the BBB are far more diverse than they were assumed to be.

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“…The results of Mori et al may provide a molecular basis for improving the permeability of thiopurine nucleobase analogs to the brain and offer an approach to reduce CNS relapses during treatment of patients with ALL. The identification of 6-MP and another antimetabolite, 5-fluorouracil (5-FU), as novel transport substrates for mOat3 was also reported by Kobayashi et al (39). K m for 6-MP was 4.01 µM and that for 5-FU was 53.9 nM.…”

Section: Novel Transport Substratesmentioning

confidence: 88%

Organic Anion Transporter Family: Current Knowledge

2006

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Abstract. Organic anion transporters (OATs) play an essential role in the elimination of numerous endogenous and exogenous organic anions from the body. The renal OATs contribute to the excretion of many drugs and their metabolites that are important in clinical medicine. Several families of multispecific organic anion and cation transporters, including OAT family transporters, have recently been identified by molecular cloning. The OAT family consists of six isoforms (OAT1 -4, URAT1, and rodent Oat5) and they are all expressed in the kidney, while some are also expressed in the liver, brain, and placenta. The OAT family represents mainly the renal secretory and reabsorptive pathway for organic anions and is also involved in the distribution of organic anions in the body, drug-drug interactions, and toxicity of anionic substances such as nephrotoxic drugs and uremic toxins. In this review, current knowledge of and recent progress in the understanding of several aspects of OAT family members are discussed.

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Renal Transport of Organic Compounds Mediated by Mouse Organic Anion Transporter 3 (Moat3): Further Substrate Specificity of Moat3

Cited by 41 publications

References 33 publications

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Sex-dependent expression of Oat3 (Slc22a8) and Oat1 (Slc22a6) proteins in murine kidneys

Organic Anion Transporter 3 Mediates the Efflux Transport of an Amphipathic Organic Anion, Dehydroepiandrosterone Sulfate, across the Blood-Brain Barrier in Mice

Organic Anion Transporter Family: Current Knowledge

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