Liver X receptor activation downregulates organic anion transporter 1 (OAT1) in the renal proximal tubule

2012 ◽  
Vol 302 (5) ◽  
pp. F552-F560 ◽  
Author(s):  
Suticha Kittayaruksakul ◽  
Sunhapas Soodvilai ◽  
Nithi Asavapanumas ◽  
Chatchai Muanprasat ◽  
Varanuj Chatsudthipong
Keyword(s):  
Proximal Tubule ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Renal Proximal Tubule ◽  
Organic Anion Transporter ◽  
Anion Transporter ◽  
X Receptors ◽  
Lxr Agonists

Liver X receptors (LXRs) play an important role in the regulation of cholesterol by regulating several transporters. In this study, we investigated the role of LXRs in the regulation of human organic anion transporter 1 (hOAT1), a major transporter localized in the basolateral membrane of the renal proximal tubule. Exposure of renal S2 cells expressing hOAT1 to LXR agonists (TO901317 and GW3965) and their endogenous ligand [22(R)-hydroxycholesterol] led to the inhibition of hOAT1-mediated [14C]PAH uptake. This inhibition was abolished by coincubation of the above agonists with 22(S)-hydroxycholesterol, an LXR antagonist. Moreover, it was found that the effect of LXR agonists was not mediated by changes in intracellular cholesterol levels. Interestingly, the inhibitory effect of LXRs was enhanced in the presence of 9- cis retinoic acid, a retinoic X receptor agonist. Kinetic analysis revealed that LXR activation decreased the maximum rate of PAH transport ( Jmax) but had no effect on the affinity of the transporter ( Kt). This result correlated well with data from Western blot analysis, which showed the decrease in hOAT1 expression following LXR activation. Similarly, TO901317 inhibited [14C]PAH uptake by the renal cortical slices as well as decreasing mOAT1 protein expression in mouse kidney. Our findings indicated for the first time that hOAT1 was downregulated by LXR activation in the renal proximal tubule.

scholarly journals Liver x receptors regulate human organic anion transporter 1 in renal proximal tubule

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Suticha Kittayaruksakul ◽  
Sunhapas Soodvilai ◽  
Nithi Asavapanumas ◽  
Varanuj Chatsudthipong
Keyword(s):  
Proximal Tubule ◽  
Organic Anion ◽  
Renal Proximal Tubule ◽  
Organic Anion Transporter ◽  
Liver X Receptors ◽  
Anion Transporter ◽  
X Receptors

Renal organic anion transporter 1 is maldistributed and diminishes in proximal tubule cells but increases in vasculature after ischemia and reperfusion

2008 ◽  
Vol 295 (6) ◽  
pp. F1807-F1816 ◽  
Author(s):  
Osun Kwon ◽  
Wei-Wei Wang ◽  
Shane Miller
Keyword(s):  
Proximal Tubule ◽  
Ischemia Reperfusion ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Kidney Injury ◽  
Organic Anion Transporter ◽  
Membrane Domain ◽  
Proximal Tubule Cells ◽  
Anion Transporter ◽  
Tubule Cells

Renal solute clearances are reduced in ischemic acute kidney injury. However, the mechanisms explaining how solute clearance is impaired have not been clarified. Recently, we reported that cadaveric renal allografts exhibit maldistribution of organic anion transporter 1 (OAT1) in proximal tubule cells after ischemia and reperfusion, resulting in impairment of PAH clearance. In the present study, we characterized renal OAT1 in detail after ischemia-reperfusion using a rat model. We analyzed renal OAT1 using confocal microscopy with a three-dimensional reconstruction of serial optical images, Western blot, and quantitative real-time RT-PCR. OAT1 was distributed to basolateral membranes of proximal tubule cells in controls. With ischemia, OAT1 decreased in basolateral membrane, especially in the lateral membrane domain, and appeared diffusely in cytoplasm. After reperfusion following 60-min ischemia, OAT1 often formed cytoplasmic aggregates. The staining for OAT1 started reappearing in lateral membrane domain 1 h after reperfusion. The basolateral membrane staining was relatively well discernable at 240 h of reperfusion. Of note, a distinct increase in OAT1 expression was noted in vasculature early after ischemia and after reperfusion. The total amount of OAT1 protein expression in the kidney diminished after ischemia-reperfusion in a duration-dependent manner until 72 h, when they began to recover. However, even at 240 h, the amount of OAT1 did not reach control levels. The kidney tissues tended to show a remarkable but transient increase in mRNA expression for OAT1 at 5 min of ischemia. Our findings may provide insights of renal OAT1 in its cellular localization and response during ischemic acute kidney injury and recovery from it.

Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+gradient

2003 ◽  
Vol 284 (4) ◽  
pp. F763-F769 ◽  
Author(s):  
Douglas H. Sweet ◽  
Lauretta M. S. Chan ◽  
Ramsey Walden ◽  
Xiao-Ping Yang ◽  
David S. Miller ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Organic Anion ◽  
Renal Proximal Tubule ◽  
Organic Anion Transporter ◽  
Xenopus Laevis Oocytes ◽  
Estrone Sulfate ◽  
Anion Transporter ◽  
Renal Proximal Tubule Cells ◽  
Rat Renal Cortical Slices ◽  
Cortical Slices

Basolateral uptake of organic anions in renal proximal tubule cells is indirectly coupled to the Na+ gradient through Na+-dicarboxylate cotransport and organic anion/dicarboxylate exchange. One member of the organic anion transporter (OAT) family, Oat1, is expressed in the proximal tubule and is an organic anion/dicarboxylate exchanger. However, a second organic anion carrier, Oat3, is also highly expressed in the renal proximal tubule, but its mechanism is unclear. Thus we have assessed Oat3 function in Xenopus laevis oocytes and rat renal cortical slices. Probenecid-sensitive uptake of p-aminohippurate (PAH, an Oat1 and Oat3 substrate) and estrone sulfate (ES, an Oat3 substrate) in rat Oat3-expressing oocytes was significantly trans-stimulated by preloading the oocytes with the dicarboxylate glutarate (GA). GA stimulation of ES transport by oocytes coexpressing rabbit Na+-dicarboxylate cotransporter 1 and rat Oat3 was significantly inhibited when the preloading medium contained Li+ or methylsuccinate (MS) or when Na+ was absent. All these treatments inhibit the Na+-dicarboxylate cotransporter, but not rat Oat3. Li+, MS, and Na+ removal had no effect when applied during the ES uptake step, rather than during the GA preloading step. Concentrative ES uptake in rat renal cortical slices was also demonstrated to be probenecid and Na+ sensitive. Accumulation of ES was stimulated by GA, and this stimulation was completely blocked by probenecid, Li+, MS, taurocholate, and removal of Na+. Thus Oat3 functions as an organic anion/dicarboxylate exchanger that couples organic anion uptake indirectly to the Na+ gradient.

scholarly journals A Human Renal Proximal Tubule Cell Line with Stable Organic Anion Transporter 1 and 3 Expression Predictive for Antiviral-Induced Toxicity

2016 ◽  
Vol 18 (2) ◽  
pp. 465-475 ◽  
Author(s):  
Tom T. G. Nieskens ◽  
Janny G. P. Peters ◽  
Marieke J. Schreurs ◽  
Niels Smits ◽  
Rob Woestenenk ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Cell Line ◽  
Organic Anion ◽  
Renal Proximal Tubule ◽  
Organic Anion Transporter ◽  
Proximal Tubule Cell ◽  
Tubule Cell ◽  
Anion Transporter

Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney

1999 ◽  
Vol 276 (1) ◽  
pp. F122-F128 ◽  
Author(s):  
Makoto Hosoyamada ◽  
Takashi Sekine ◽  
Yoshikatsu Kanai ◽  
Hitoshi Endou
Keyword(s):  
Proximal Tubule ◽  
Organic Anion ◽  
Basolateral Membrane ◽  
Human Kidney ◽  
Organic Anion Transporter ◽  
Renal Elimination ◽  
Xenopus Laevis Oocytes ◽  
Cdna Clones ◽  
Phenol Red ◽  
Anion Transporter

Recently, we isolated the multispecific organic anion transporter (OAT1) from the rat kidney, which plays important roles in the renal elimination of endogenous and exogenous organic anions including clinically important drugs. In the present study, we cloned and characterized human OAT1. Two cDNA clones, hOAT1–1 cDNA and hOAT1–2 cDNA, were isolated from a human kidney cDNA library, whose amino acid sequences were 86.0% and 87.8% identical to that of rat OAT1, respectively. When expressed in Xenopus laevis oocytes, hOAT1 mediated sodium-independent uptake of p-aminohippurate (PAH) ( K m = 9.3 ± 1.0 μM). hOAT1-mediated PAH uptake was inhibited by bulky inorganic anions, various xenobiotics, and endogenous substances, including benzylpenicillin, furosemide, indomethacin, probenecid, phenol red, urate, and α-ketoglutarate. Northern blot analysis revealed that hOAT1 mRNA is strongly expressed in human kidney; transcripts of different sizes are expressed in skeletal muscle, brain, and placenta. Immunohistochemical analysis using rabbit IgG antibody against the carboxy-terminal 14 peptides of hOAT1 revealed that hOAT1 is expressed at the basolateral membrane of the proximal tubule. hOAT1 gene was located on human chromosome 11q13.1 by fluorescent in situ hybridization analysis. These results indicate that hOAT1 is a multispecific organic anion transporter on the basolateral membrane of the proximal tubule in human kidney.

scholarly journals Identification of a Novel Voltage-driven Organic Anion Transporter Present at Apical Membrane of Renal Proximal Tubule

2003 ◽  
Vol 278 (30) ◽  
pp. 27930-27938 ◽  
Author(s):  
Promsuk Jutabha ◽  
Yoshikatsu Kanai ◽  
Makoto Hosoyamada ◽  
Arthit Chairoungdua ◽  
Do Kyung Kim ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Apical Membrane ◽  
Organic Anion ◽  
Renal Proximal Tubule ◽  
Organic Anion Transporter ◽  
Anion Transporter

Hypouricemic Effects ofArmillaria melleaon Hyperuricemic Mice Regulated through OAT1 and CNT2

2018 ◽  
Vol 46 (03) ◽  
pp. 585-599 ◽  
Author(s):  
Tianqiao Yong ◽  
Shaodan Chen ◽  
Yizhen Xie ◽  
Diling Chen ◽  
Jiyan Su ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Glucose Transporter ◽  
Organic Anion ◽  
Inhibitory Effect ◽  
Organic Anion Transporter ◽  
Nucleoside Transporter ◽  
Inhibitory Effects ◽  
Concentrative Nucleoside Transporter ◽  
Anion Transporter ◽  
Glucose Transporter 9

Ethanol and water extracts of Armillaria mellea were prepared by directly soaking A. mellea in ethanol (AME) at 65[Formula: see text]C, followed by decocting the remains in water (AMW) at 85[Formula: see text]C. Significantly, AME and AMW at 30, 60 and 120[Formula: see text]mg/kg exhibited excellent hypouricemic actions, causing remarkable declines from hyperuricemic control (351[Formula: see text][Formula: see text]mol/L, [Formula: see text]) to 136, 130 and 115[Formula: see text][Formula: see text]mol/L and 250, 188 and 152[Formula: see text][Formula: see text]mol/L in serum uric acid, correspondingly. In contrast to the evident renal toxicity of allopurinol, these preparations showed little impacts. Moreover, they showed some inhibitory effect on XOD (xanthine oxidase) activity. Compared with hyperuricemic control, protein expressions of OAT1 (organic anion transporter 1) were significantly elevated in AME- and AMW-treated mice. The levels of GLUT9 (glucose transporter 9) expression were significantly decreased by AMW. CNT2 (concentrative nucleoside transporter 2), a key target for purine absorption in gastrointestinal tract was involved in this study, and was verified for its innovative role. Both AME and AMW down-regulated CNT2 proteins in the gastrointestinal tract in hyperuricemic mice. As they exhibited considerable inhibitory effects on XOD, we selected XOD as the target for virtual screening by using molecular docking, and four compounds were hit with high ranks. From the analysis, we concluded that hydrogen bond, Pi–Pi and Pi-sigma interactions might play important roles for their orientations and locations in XOD inhibition.

scholarly journals A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

2012 ◽  
Vol 302 (10) ◽  
pp. F1293-F1299 ◽  
Author(s):  
Volker Vallon ◽  
Satish A. Eraly ◽  
Satish Ramachandra Rao ◽  
Maria Gerasimova ◽  
Michael Rose ◽  
...  
Keyword(s):  
Organic Anion ◽  
Basolateral Membrane ◽  
Tubular Secretion ◽  
Organic Anion Transporter ◽  
Xenopus Laevis Oocytes ◽  
Mean Values ◽  
Anion Transporters ◽  
Anion Transporter ◽  
Neutral Compounds ◽  
Quantitative Contribution

Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 ( Oat1−/−) and OAT3 ( Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.

Stereoselective Inhibition of Renal Basolateral Human Organic Anion Transporter 3 by Lansoprazole Enantiomers

Pharmacology ◽  
2018 ◽  
Vol 101 (3-4) ◽  
pp. 176-183 ◽  
Author(s):  
Yugo Hamada ◽  
Kenji Ikemura ◽  
Takuya Iwamoto ◽  
Masahiro Okuda
Keyword(s):  
Cultured Cells ◽  
Organic Anion ◽  
Inhibitory Effect ◽  
Organic Anion Transporter ◽  
Racemic Mixture ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Anion Transporter ◽  
Ic50 Value ◽  
Organic Anion Transporter 3

Lansoprazole, a proton pump inhibitor, potently inhibits human organic anion transporter, hOAT3 (SLC22A8). Lansoprazole has an asymmetric atom in its structure and is clinically administered as a racemic mixture of (R)-and (S)-enantiomers. However, little is known about the stereoselective inhibitory potencies of lansoprazole against hOAT3 and its homolog, hOAT1. In the present study, the stereoselective inhibitory effect of lansoprazole was evaluated using hOAT1-and hOAT3-expressing cultured cells. hOAT1 and hOAT3 transported [14C]p-aminohippurate and [3H]estrone-3-sulfate (ES) with Michaelis-Menten constants of 29.8 ± 4.0 and 30.1 ± 9.0 µmol/L respectively. Lansoprazole enantiomers inhibited hOAT1- and hOAT3-mediated transport of each substrate in a concentration-dependent manner. The IC50 value of (S)-lansoprazole against hOAT3-mediated transport of [3H]ES (0.61 ± 0.08 µmol/L) was significantly lower than that of (R)-lansoprazole (1.75 ± 0.31 µmol/L). In contrast, stereoselectivity was not demonstrated for the inhibition of hOAT1. Furthermore, (S)-lansoprazole inhibited hOAT3-mediated transport of pemetrexed and methotrexate (hOAT3 substrates) more strongly than the corresponding (R)-lansoprazole. This study is the first to demonstrate that the stereoselective inhibitory potency of (S)-lansoprazole against hOAT3 is greater than that of (R)-lansoprazole. The present findings provide novel information about the drug interactions associated with lansoprazole.

scholarly journals Peritubular transport of ochratoxin A by single rabbit renal proximal tubules.

1998 ◽  
Vol 9 (11) ◽  
pp. 1973-1982 ◽  
Author(s):  
J R Welborn ◽  
C E Groves ◽  
S H Wright
Keyword(s):  
Proximal Tubule ◽  
Ochratoxin A ◽  
Organic Anion ◽  
High Capacity ◽  
Organic Anion Transporter ◽  
Epifluorescence Microscopy ◽  
Proximal Tubule Cells ◽  
Anion Transporter ◽  
Uptake Medium ◽  
Proximal Tubule Segments

Epifluorescence microscopy was used to study peritubular transport of the fluorescent mycotoxin ochratoxin A (OTA) into single proximal tubule segments of the rabbit. Initial rates of OTA uptake into S2 segments were saturable and adequately described by Michaelis-Menten kinetics, with an apparent Km of 2.2+/-0.3 microM (SEM). Several lines of evidence indicated that peritubular uptake of OTA in S2 segments was effectively limited to the "classical" organic anion transporter. First, 5 mM p-aminohippurate (PAH) cis-inhibited the uptake of 1 microM OTA into tubules by 96%. Kinetic analysis of the inhibition of OTA uptake by PAH (100 microM to 5 mM) yielded an apparent Ki of 164 microM, similar to the 100 to 200 microM range of Km values previously reported for the peritubular uptake of PAH. Second, efflux of OTA from tubules was trans-stimulated 3.2-fold by the presence of 2.5 mM PAH in the uptake medium. Third, 100 microM alpha-ketoglutarate (alphaKG) trans-stimulated the uptake rate of 1 microM OTA by 1.8-fold. Fourth, besides PAH, other organic anions effectively cis-inhibited the uptake of 1 microM OTA into tubules (inhibitor, % inhibition): 1.5 mM alphaKG, 80%; 1 mM probenecid, 100%; 1 mM piroxicam, 100%; 1 mM octanoate, 100%. In contrast, 1.5 mM tetraethylammonium, an organic cation, blocked uptake of 1 microM OTA by only 7%. The inhibition of OTA uptake into S1 and S3 segments of the proximal tubule was qualitatively similar: 5 mM PAH cis-inhibited the uptake of 1 microM OTA by approximately 95% in both S1 and S3 segments. Thus, peritubular OTA uptake into all segments of the proximal tubule appears to be dominated by its interaction with the classical organic anion transporter. The high-affinity and relatively high capacity of this pathway for OTA suggest that peritubular uptake may be a significant avenue for the entry of this toxin into proximal tubule cells.

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