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

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.

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

Activation of liver X receptors reduces CFTR-mediated Cl− transport in kidney collecting duct cells

2013 ◽  
Vol 305 (4) ◽  
pp. F583-F591 ◽  
Author(s):  
Promporn Raksaseri ◽  
Varanuj Chatsudthipong ◽  
Chatchai Muanprasat ◽  
Sunhapas Soodvilai
Keyword(s):  
Mdck Cell ◽  
Cell Model ◽  
Collecting Duct ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Type I ◽  
Liver X Receptors ◽  
Cell Monolayers ◽  
Anion Transporter ◽  
X Receptors

Liver X receptors (LXRs) are transcription factors belonging to the nuclear receptor super family, which act as regulators of lipid and glucose metabolism. However, LXRs have been shown to regulate the function of transporters in the kidney, including the Na-Pi cotransporter, organic anion transporter, and epithelial Na+ channel. In this report, we demonstrated the ability of LXR ligands, both endogenous [22 ( R)-hydroxycholesterol] and synthetic (T0901317 and GW3965), to reduce CFTR-mediated Cl− secretion in a type I Madin-Darby canine kidney (MDCK) cell line and in murine primary inner medullary collecting duct (IMCD) cells, based on measurements of [Arg8]-vasopressin-induced Cl− current. However, treatment of MDCK cell monolayers with 5 μM T0901317 for 24 h did not alter ouabain-senstive current or Na+-K+-ATPase-α protein content. Furthermore, basolateral membranes permeabilization of MDCK cell monolayers still resulted in a decrease in apical Cl− current stimulated by both [Arg8]-vasopressin and 8-cholorophenyl-thio-cAMP, indicating that the factor(s) encoded by the target gene(s) of agonist-activated LXRs might be located at the apical membrane. Western blot analysis revealed that inhibition of Cl− secretion occurred via a decrease in CFTR protein, which was not due to downregulation of its mRNA expression. In addition, both synthetic LXR agonists significantly retarded the growth of forskolin-induced cysts formed in MDCK cells cultured in collagen gel. This is the first evidence showing that ligand-activated LXRs are capable of downregulating CFTR-mediated Cl− secretion of kidney cells and of retarding cyst growth in a MDCK cell model.

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

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.

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.

scholarly journals Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion

2019 ◽  
Vol 116 (32) ◽  
pp. 16105-16110 ◽  
Author(s):  
Jitske Jansen ◽  
Katja Jansen ◽  
Ellen Neven ◽  
Ruben Poesen ◽  
Amr Othman ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Gut Microbiome ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Indoxyl Sulfate ◽  
Regulation Mechanism ◽  
Uremic Toxin ◽  
Proximal Tubule Cell ◽  
Anion Secretion ◽  
Anion Transporter

Membrane transporters and receptors are responsible for balancing nutrient and metabolite levels to aid body homeostasis. Here, we report that proximal tubule cells in kidneys sense elevated endogenous, gut microbiome-derived, metabolite levels through EGF receptors and downstream signaling to induce their secretion by up-regulating the organic anion transporter-1 (OAT1). Remote metabolite sensing and signaling was observed in kidneys from healthy volunteers and rats in vivo, leading to induced OAT1 expression and increased removal of indoxyl sulfate, a prototypical microbiome-derived metabolite and uremic toxin. Using 2D and 3D human proximal tubule cell models, we show that indoxyl sulfate induces OAT1 via AhR and EGFR signaling, controlled by miR-223. Concomitantly produced reactive oxygen species (ROS) control OAT1 activity and are balanced by the glutathione pathway, as confirmed by cellular metabolomic profiling. Collectively, we demonstrate remote metabolite sensing and signaling as an effective OAT1 regulation mechanism to maintain plasma metabolite levels by controlling their secretion.

scholarly journals Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity

2018 ◽  
Vol 46 (5) ◽  
pp. 592-599 ◽  
Author(s):  
Tom T. G. Nieskens ◽  
Janny G. P. Peters ◽  
Dina Dabaghie ◽  
Daphne Korte ◽  
Katja Jansen ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Organic Anion ◽  
Human Kidney ◽  
Organic Anion Transporter ◽  
Proximal Tubule Cells ◽  
Kidney Proximal Tubule ◽  
Anion Transporter ◽  
Cisplatin Sensitivity ◽  
Tubule Cells

scholarly journals Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules.

1997 ◽  
Vol 8 (8) ◽  
pp. 1213-1221 ◽  
Author(s):  
T P Schaub ◽  
J Kartenbeck ◽  
J König ◽  
O Vogel ◽  
R Witzgall ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Laser Scanning ◽  
Apical Membrane ◽  
Rat Kidney ◽  
Organic Anion ◽  
Laser Scanning Microscopy ◽  
Organic Anion Transporter ◽  
Confocal Laser ◽  
Membrane Domain ◽  
Anion Transporter

A novel ATP-dependent export pump for amphiphilic anionic conjugates, which has been cloned recently from liver, was identified in rat kidney and localized to the apical membrane domain of proximal tubule epithelia. This 190-kD membrane glycoprotein (Mrp2) has been described previously as the hepatocyte canalicular isoform of the multidrug resistance protein and as the canalicular multispecific organic anion transporter. Mrp2 was identified in kidney by reverse transcription PCR followed by sequencing of the amplified 786-bp fragment and by immunoblotting, using an antibody specifically reacting with the carboxy terminus of rat Mrp2. Double immunofluorescence and confocal laser-scanning microscopy showed the presence of Mrp2 in the brush-border membrane domain of segments S1, S2, and S3 of proximal tubule epithelia. Mrp2 was not detectable in other segments of the nephron. The onset of Mrp2 expression during development occurred in a very early stage of nephron development. Mrp2 represents the first cloned ATP-dependent export pump for amphiphilic organic anions identified in kidney and localized to the apical membrane domain of proximal tubule epithelia. Mrp2 may contribute to cellular detoxification and to the secretion of endogenous and xenobiotic anionic substances, most of which are conjugates, from the blood into urine.

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