Journal articles: 'OAT15A'

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Zhang, Yufei, Pu Yang, Runze Li, and Haixin Chen. "Unsteady Simulation of Transonic Buffet of a Supercritical Airfoil with Shock Control Bump." Aerospace 8, no. 8 (July 26, 2021): 203. http://dx.doi.org/10.3390/aerospace8080203.

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The unsteady flow characteristics of a supercritical OAT15A airfoil with a shock control bump were numerically studied by a wall-modeled large eddy simulation. The numerical method was first validated by the buffet and nonbuffet cases of the baseline OAT15A airfoil. Both the pressure coefficient and velocity fluctuation coincided well with the experimental data. Then, four different shock control bumps were numerically tested. A bump of height h/c = 0.008 and location xB/c = 0.55 demonstrated a good buffet control effect. The lift-to-drag ratio of the buffet case was increased by 5.9%, and the root mean square of the lift coefficient fluctuation was decreased by 67.6%. Detailed time-averaged flow quantities and instantaneous flow fields were analyzed to demonstrate the flow phenomenon of the shock control bumps. The results demonstrate that an appropriate “λ” shockwave pattern caused by the bump is important for the flow control effect.

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Huang, JingBo, ZhiXiang Xiao, Jian Liu, and Song Fu. "Simulation of shock wave buffet and its suppression on an OAT15A supercritical airfoil by IDDES." Science China Physics, Mechanics and Astronomy 55, no. 2 (January 11, 2012): 260–71. http://dx.doi.org/10.1007/s11433-011-4601-9.

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Accorinti, Alessandro, Tim Baur, Sven Scharnowski, Johannes Knebusch, Johannes Dillinger, Yves Govers, Jens Nitzsche, and Christian J. Kahler. "Measurements of deformation, schlieren and forces on an OAT15A airfoil at pre-buffet and buffet conditions." IOP Conference Series: Materials Science and Engineering 1024, no. 1 (January 1, 2021): 012052. http://dx.doi.org/10.1088/1757-899x/1024/1/012052.

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Geoghegan, Jack A., Nicholas F. Giannelis, and Gareth A. Vio. "A Numerical Investigation of the Geometric Parametrisation of Shock Control Bumps for Transonic Shock Oscillation Control." Fluids 5, no. 2 (April 10, 2020): 46. http://dx.doi.org/10.3390/fluids5020046.

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At transonic flight conditions, shock oscillations on wing surfaces are known to occur and result in degraded aerodynamic performance and handling qualities. This is a purely flow-driven phenomenon, known as transonic buffet, that causes limit cycle oscillations and may present itself within the operational flight envelope. Hence, there is significant research interest in the development of shock control techniques to either stabilise the unsteady flow or raise the boundary onset. This paper explores the efficacy of dynamically activated contour-based shock control bumps within the buffet envelope of the OAT15A aerofoil on transonic flow control numerically through unsteady Reynolds-averaged Navier–Stokes modelling. A parametric evaluation of the geometric variables that define the Hicks–Henne-derived shock control bump will show that bumps of this type lead to a large design space of applicable shapes for buffet suppression. Assessment of the flow field, local to the deployed shock control bump geometries, reveals that control is achieved through a weakening of the rear shock leg, combined with the formation of dual re-circulatory cells within the separated shear-layer. Within this design space, favourable aerodynamic performance can also be achieved. The off-design performance of two optimal shock control bump configurations is explored over the buffet region for M = 0.73, where the designs demonstrate the ability to suppress shock oscillations deep into the buffet envelope.

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Youngblood, Geri L., and Douglas H. Sweet. "Identification and functional assessment of the novel murine organic anion transporter Oat5 (Slc22a19) expressed in kidney." American Journal of Physiology-Renal Physiology 287, no. 2 (August 2004): F236—F244. http://dx.doi.org/10.1152/ajprenal.00012.2004.

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An uncharacterized murine cDNA clone was identified and, through sequence, phylogenetic, and functional analysis, determined to encode the newest member of the organic anion transporter family, organic anion transporter 5 (Oat5; Slc22a19). The Oat5 cDNA clone contained an insert 1,964 bp in length with a predicted open reading frame (from bp 84 to bp 1,739) coding for a peptide 551 amino acids long. Slc22a19 was localized to mouse chromosome 19 near the genes encoding Oat1 ( Slc22a6) and Oat3 ( Slc22a8). Northern blot analysis revealed Oat5 is highly expressed in the kidney of adult mice and rats. No sexual dimorphism in renal or hepatic expression of Oat5 was observed. Unlike Oat1–3, Oat5 expression was not detected in the choroid plexus of either mice or rats. Murine Oat5-expressing Xenopus laevis oocytes supported increased accumulation of the mycotoxin ochratoxin A, compared with water-injected control oocytes. This uptake was significantly inhibited by probenecid and the organic anions 2,4-dichlorophenoxyacetic acid, salicylate, and estrone sulfate but not by para-aminohippurate or urate. Transport of ochratoxin A by murine Oat5 was saturable, with an estimated Km of 2.0 ± 0.45 μM. Oat5-mediated transport was neither cis-inhibited nor trans-stimulated by the dicarboxylate glutarate. Uptake was also completely unaffected by short-circuiting of the membrane potential. Thus the motive forces behind Oat5 function, which provide insight into its membrane localization, need to be further resolved. These data demonstrate for the first time that this newly identified gene encodes a protein that functions as an organic anion transporter.

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Brzica, Hrvoje, Davorka Breljak, Marija Ljubojević, Daniela Balen, Vedran Micek, Naohiko Anzai, and Ivan Sabolić. "Optimal Methods of Antigen Retrieval for Organic Anion Transporters in Cryosections of the Rat Kidney." Archives of Industrial Hygiene and Toxicology 60, no. 1 (March 1, 2009): 7–17. http://dx.doi.org/10.2478/10004-1254-60-2009-1895.

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Optimal Methods of Antigen Retrieval for Organic Anion Transporters in Cryosections of the Rat KidneyTo localise antigens by immunocytochemistry (IC), the samples of tissues or cells are usually denatured by fixation, and either frozen and cryosectioned, or embedded in paraffin before sectioning. p-Formaldehyde (PFA; formalin) is a common fixative, which preserves antigenicity of proteins, but damages the tissue/cell morphology and "masks" the antibody binding sites (epitopes). In order to "unmask" epitopes, some kind of antigen retrieval (AR) is used. The aim of this study was: a) to find an optimal AR method in cryosections of in vivo PFA-fixed kidneys for organic anion transporters (Oat) that reside in the basolateral (Oat1, Oat3) and brush-border membrane (Oat2, Oat5) of the rat renal proximal tubules, and b) using optimal method, to compare IC staining of Oats in kidneys that had been PFA-fixed in vivo or in vitro. IC staining in untreated cryosections was compared with that following detergent treatment or microwave heating in citrate buffer of pH 3, pH 6, or pH 8, with or without alcohol pre-treatment. The preferred AR method for Oat1, Oat2, and Oat5 was heating of cryosections at pH 6, and for Oat3 heating at pH 3, without alcohol pre-treatment. Compared with tissue fixed in vivo, tissue fixed in vitro exhibited damaged tubule morphology, similar staining intensity of Oat1 and Oat3, and higher staining intensity of Oat2 and Oat5. We conclude that for optimal IC presentation, each Oat in the rat kidney has to be treated individually, with different fixation and AR approach.

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Kwabiah, A. B., D. Spaner, and A. G. Todd. "Shoot-to-root ratios and root biomass of cool-season feed crops in a boreal Podzolic soil in Newfoundland." Canadian Journal of Soil Science 85, no. 3 (August 1, 2005): 369–76. http://dx.doi.org/10.4141/s02-032.

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Barley (Hordeum vulgare L.) and oat (Avena sativa L.) crops are grown as feed grains by Newfoundland (NL) dairy farmers. The cereals are either grown as monoculture or intercropped with field pea (Pisum sativum L.) with or without N fertilization. Two experiments were conducted in both 2000 and 2001 to evaluate the shoot-to-root (S:R) weight ratios and root biomass in these production systems. Experiment 1 involved monocultures of pea sown at 150 kg ha-1, and barley and oat each sown at 170 kg ha-1. For pea-barley and pea-oat intercrops, pea was sown at 150 kg ha-1 and each cereal component was sown at either 85 and 170 kg ha-1. The seven treatments were referred to, respectively, as pea150, barley170, oat170, pea150-barley85, pea150-oat85, pea150-barley170, and pea150-oat170. Experiment 2 evaluated factorial combinations of two barley seeding rates of 107 kg ha-1 (low) and 157 kg ha-1 (high) and three N rates (0, 30 and 60 kg ha-1) applied at Zadok’s Growth Stage (ZGS 30). Root biomass was sampled from soil (30-cm depth) and determined at about the anthesis stage of oat and barley and the shoot biomass at maturity (ZGS 90). In exp.1, the S:R ratios of oat170 and pea150-oat85and pea150-oat170 ranged from 8.1 to 8.8 and were lower than barley170, pea150, pea150-barley85and pea150-barley170 which ranged from 10.0 to 12.5. Barley170 had the highest root biomass of 835 kg ha-1 followed by pea150-barley170 (745 kg ha-1) and pea150-oat170 (765 kg ha-1). Intercropping pea with cereals increased root biomas s by 31% for pea150-barley85and 48% for pea150-oat85compared to pea150. However, root biomass increased by 109% for pea150-barley170 and 104% for pea150-oat170, indicating that the cereal component of the intercrops contributed more to the root biomass than the pea at the higher seeding rate of the cereal crop. In exp. 2, the 0 kg N ha-1 rate produced the lowest S:R ratios irrespective of the barley seeding rate. When N was applied, both the shoot biomass and root biomass appeared to be increased at the high barley seeding rate. The feed grain production practice in Newfoundland could affect root biomass production in soil. High cereal seeding rates in either monoculture and intercrop systems are required to maximize root biomass production and therefore increase C inputs into the soil. Key words: Shoot-to-root (S:R) ratios, root biomass, intercrops, barley, oat, pea, seeding rate

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Olszewski-Hamilton, U., M. Svoboda, T. Thalhammer, V. Buxhofer-Ausch, K. Geissler, and G. Hamilton. "Organic Anion Transporting Polypeptide 5A1 (OATP5A1) in Small Cell Lung Cancer (SCLC) Cells: Possible Involvement in Chemoresistance to Satraplatin." Biomarkers in Cancer 3 (January 2011): BIC.S7151. http://dx.doi.org/10.4137/bic.s7151.

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Background The role of organic anion transporting polypeptide 5A1 (OATP5A1) a member of a family of drug transporters that mediate cellular uptake of drugs has not been characterized so far. Methods Gene expression levels of OATP5A1 in small cell lung cancer (SCLC) cell lines were determined by real-time qPCR and chemosensitivity of HEK-293- SLCO5A1-transfected cells to satraplatin in MTT assays. Results Significant expression of this transporter was found at the mRNA level, primarily in drug-resistant SCLC cells, and SLCO5A1-transfected HEK-293 cells showed higher resistance to satraplatin. OATP5A1 is found preferentially in cytoplasmic membranes of tumor cells, including SCLC. Conclusions OATP5A1 seems to effect intracellular transport of drugs and may participate in chemoresistance of SCLC by sequestration, rather than mediating cellular uptake. Since satraplatin failed to improve survival in SCLC patients, the relation of OATP5A1 expression to clinical drug resistance and its use as marker of chemoresistance should be further investigated.

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Wu, Wei, Michael E. Baker, Satish A. Eraly, Kevin T. Bush, and Sanjay K. Nigam. "Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members." Physiological Genomics 38, no. 2 (July 2009): 116–24. http://dx.doi.org/10.1152/physiolgenomics.90309.2008.

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When the organic anion transporter Oat1 was first identified as NKT (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, Nigam SK. J Biol Chem 272: 6471–6478, 1997), it was argued that it, together with Oct1, may be part of a larger subfamily (now known as SLC22) involved in organic ion and xenobiotic transport. The least studied among SLC22 transporters are the so-called unknown substrate transporters ( USTs). Here, five novel genes located in a cluster on mouse chromosome 19, immediately between Slc22a8 ( Oat3)/ Slc22a6 ( Oat1) and Slc22a19 ( Oat5), were identified as homologs of human USTs. These genes display preferential expression in liver and kidney, and one gene, AB056422, has several splicing variants with differential tissue expression and embryonic expression. Along with Slc22a6, Slc22a8, and Slc22a19, these Usts define the largest known cluster of mammalian Slc22 genes. Given the established functions of Oats, these genes may also be involved in organic anion transport. Usts have characteristic motifs and share a signature residue in the possible active site of transmembrane domain 7, a conserved, positively charged, amino acid, Arg356, possibly a site for interaction with organic anions. In certain species, Oat1 and Oat3 appeared to be highly conserved, whereas the Ust part of this cluster appeared to undergo repeated species-specific amplification, suggesting strong environmental selection pressure, and perhaps providing an explanation for copy number variation in the human locus. One Ust amplification in mouse appears to be recent. This cluster may be coordinately regulated and under selective pressure in a species-specific manner.

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Durmus, Selvi, Jyoti Naik, Levi Buil, Els Wagenaar, Olaf van Tellingen, and Alfred H. Schinkel. "In vivodisposition of doxorubicin is affected by mouse Oatp1a/1b and human OATP1A/1B transporters." International Journal of Cancer 135, no. 7 (March 4, 2014): 1700–1710. http://dx.doi.org/10.1002/ijc.28797.

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Gottier Nwafor, Janine, Marta Nowik, Naohiko Anzai, Hitoshi Endou, and Carsten A. Wagner. "Metabolic Acidosis Alters Expression of Slc22 Transporters in Mouse Kidney." Kidney and Blood Pressure Research 45, no. 2 (2020): 263–74. http://dx.doi.org/10.1159/000506052.

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Introduction: The kidneys play a central role in eliminating metabolic waste products and drugs through transporter-mediated excretion along the proximal tubule. This task is mostly achieved through a variety of transporters from the solute carrier family 22 (SLC22) family of organic cation and anion transporters. Metabolic acidosis modulates metabolic and renal functions and also affects the clearance of metabolites and drugs from the body. We had previously shown that induction of metabolic acidosis in mice alters a large set of transcripts, among them also many transporters including transporters from the Slc22 family. Objective: Here we further investigated the impact of acidosis on Slc22 family members. Methods: Metabolic acidosis was induced for 2 or 7 days with NH4Cl, some animals also received the uricase inhibitor oxonic acid for comparison. Expression of transporters was studied by qPCR and immunoblotting. Results: NH4Cl induced no significant changes in plasma or urine uric acid levels but caused downregulation of Slc22a1 (Oct1), Slc22a6 (Oat1), Slc22a19 (Oat5), and Slc22a12 (Urat1) at mRNA level. In contrast, Slc22a4 mRNA (Octn1) was upregulated. On protein level, NH4Cl increased Octn1 (after 7 days) and Urat1 (after 2 days) abundance and decreased Oat1 (after 2 days) and Urat1 (after 7 days). Oxonic acid had no impact on protein abundance of any of the transporters tested. Conclusion: In summary, metabolic acidosis alters expression of several transporters involved in renal excretion of metabolic waste products and drugs. This may have implications for drug kinetics and clearance of waste metabolites.

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Aslamkhan, Amy G., Deborah M. Thompson, Jennifer L. Perry, Kelly Bleasby, Natascha A. Wolff, Scott Barros, David S. Miller, and John B. Pritchard. "The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 291, no. 6 (December 2006): R1773—R1780. http://dx.doi.org/10.1152/ajpregu.00326.2006.

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The flounder renal organic anion transporter (fOat) has substantial sequence homology to mammalian basolateral organic anion transporter orthologs (OAT1/Oat1 and OAT3/Oat3), suggesting that fOat may have functional properties of both mammalian forms. We therefore compared uptake of various substrates by rat Oat1 and Oat3 and human OAT1 and OAT3 with the fOat clone expressed in Xenopus oocytes. These data confirm that estrone sulfate is an excellent substrate for mammalian OAT3/Oat3 transporters but not for OAT1/Oat1 transporters. In contrast, 2,4-dichlorophenoxyacetic acid and adefovir are better transported by mammalian OAT1/Oat1 than by the OAT3/Oat3 clones. All three substrates were well transported by fOat-expressing Xenopus oocytes. fOat Km values were comparable to those obtained for mammalian OAT/Oat1/3 clones. We also characterized the ability of these substrates to inhibit uptake of the fluorescent substrate fluorescein in intact teleost proximal tubules isolated from the winter flounder ( Pseudopleuronectes americanus) and killifish ( Fundulus heteroclitus). The rank order of the IC50 values for inhibition of cellular fluorescein accumulation was similar to that for the Km values obtained in fOat-expressing oocytes, suggesting that fOat may be the primary teleost renal basolateral Oat. Assessment of the zebrafish ( Danio rerio) genome indicated the presence of a single Oat (zfOat) with similarity to both mammalian OAT1/Oat1 and OAT3/Oat3. The puffer fish ( Takifugu rubripes) also has an Oat (pfOat) similar to mammalian OAT1/Oat1 and OAT3/Oat3 members. Furthermore, phylogenetic analyses argue that the teleost Oat1/3-like genes diverged from a common ancestral gene in advance of the divergence of the mammalian OAT1/Oat1, OAT3/Oat3, and, possibly, Oat6 genes.

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Astorga, Bethzaida, Theresa M. Wunz, Mark Morales, Stephen H. Wright, and Ryan M. Pelis. "Differences in the substrate binding regions of renal organic anion transporters 1 (OAT1) and 3 (OAT3)." American Journal of Physiology-Renal Physiology 301, no. 2 (August 2011): F378—F386. http://dx.doi.org/10.1152/ajprenal.00735.2010.

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This study examined the selectivity of organic anion transporters OAT1 and OAT3 for structural congeners of the heavy metal chelator 2,3-dimercapto-1-propanesulfonic acid (DMPS). Thiol-reactive reagents were also used to test structural predictions based on a homology model of OAT1 structure. DMPS was near equipotent in its ability to inhibit OAT1 (IC50 = 83 μM) and OAT3 (IC50 = 40 μM) expressed in Chinese hamster ovary cells. However, removal of a thiol group (3-mercapto-1-propanesulfonic acid) resulted in a 2.5-fold increase in IC50 toward OAT1 vs. a ∼55-fold increase in IC50 toward OAT3. The data suggested that compound volume/size is important for binding to OAT1/OAT3. The sensitivity to HgCl2 of OAT1 and OAT3 was also dramatically different, with IC50 values of 104 and 659 μM, respectively. Consistent with cysteines of OAT1 being more accessible from the external medium than those of OAT3, thiol-reactive reagents reacted preferentially with OAT1 in cell surface biotinylation assays. OAT1 was less sensitive to HgCl2 inhibition and less reactive toward membrane-impermeant thiol reactive reagents following mutation of cysteine 440 (C440) to an alanine. These data indicate that C440 in transmembrane helix 10 of OAT1 is accessible from the extracellular space. Indeed, C440 was exposed to the aqueous phase of the presumptive substrate translocation pathway in a homology model of OAT1 structure. The limited thiol reactivity in OAT3 suggests that the homologous cysteine residue (C428) is less accessible. Consistent with their homolog-specific selectivities, these data highlight structural differences in the substrate binding regions of OAT1 and OAT3.

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Wegner, Waja, Gerhard Burckhardt, and Maja Henjakovic. "Transcriptional regulation of human organic anion transporter 1 by B-cell CLL/lymphoma 6." American Journal of Physiology-Renal Physiology 307, no. 11 (December 1, 2014): F1283—F1291. http://dx.doi.org/10.1152/ajprenal.00426.2014.

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The human organic anion transporter 1 (OAT1) is crucial for the excretion of organic anions in renal proximal tubular cells and has been classified as a clinically relevant transporter in the kidneys. Our previous study indicated that renal male-predominant expression of rat Oat1 and Oat3 appears to be regulated by transcription factor B-cell CLL/lymphoma 6 (BCL6). The aim of this study was to characterize the effect of BCL6 on human OAT1 promoter and on the transcription of OAT1 mediated by hepatocyte nuclear factor-1α (HNF-1α). Luciferase assays were carried out in opossum kidney (OK) cells transiently transfected with promoter constructs of OAT1, expression vectors for BCL6 and HNF-1α, and the empty control vectors. BCL6 and HNF-1α binding on OAT1 promoter was analyzed using electrophoretic mobility shift assay (EMSA). Protein expression of HNF-1α was investigated by Western blot analysis. Site-directed mutagenesis was used to introduce mutations into BCL6 and HNF-1α binding sites within the OAT1 promoter. BCL6 enhanced the promoter activity of OAT1 independently of predicted BCL6 binding sites but was dependent on HNF-1α response element and HNF-1α protein. Coexpression of BCL6 and HNF-1α induced an additive effect on OAT1 promoter activation compared with BCL6 or HNF-1α alone. BCL6 does not bind directly or indirectly to OAT1 promoter but increases the protein expression of HNF-1α and thereby indirectly enhances OAT1 gene transcription. BCL6 constitutes a promising candidate gene for the regulation of human OAT1 transcription and other renal and/or hepatic drug transporters that have been already shown to be activated by HNF-1α.

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Kwon, Osun, Wei-Wei Wang, and Shane Miller. "Renal organic anion transporter 1 is maldistributed and diminishes in proximal tubule cells but increases in vasculature after ischemia and reperfusion." American Journal of Physiology-Renal Physiology 295, no. 6 (December 2008): F1807—F1816. http://dx.doi.org/10.1152/ajprenal.90409.2008.

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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.

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Lu, Hang, Zhiqiang Lu, Xue Li, Gentao Li, Yilin Qiao, Robert P. Borris, and Youcai Zhang. "Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions." PeerJ 5 (May 25, 2017): e3333. http://dx.doi.org/10.7717/peerj.3333.

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BackgroundHerb-drug interactions (HDIs) resulting from concomitant use of herbal products with clinical drugs may cause adverse reactions. Organic anion transporter 1 (OAT1) and 3 (OAT3) are highly expressed in the kidney and play a key role in the renal elimination of substrate drugs. So far, little is known about the herbal extracts that could modulate OAT1 and OAT3 activities.MethodsHEK293 cells stably expressing human OAT1 (HEK-OAT1) and OAT3 (HEK-OAT3) were established and characterized. One hundred seventy-two extracts from 37 medicinal and economic plants were prepared. An initial concentration of 5 µg/ml for each extract was used to evaluate their effects on 6-carboxylfluorescein (6-CF) uptake in HEK-OAT1 and HEK-OAT3 cells. Concentration-dependent inhibition studies were conducted for those extracts with more than 50% inhibition to OAT1 and OAT3. The extract ofJuncus effusus, a well-known traditional Chinese medicine, was assessed for its effect on thein vivopharmacokinetic parameters of furosemide, a diuretic drug which is a known substrate of both OAT1 and OAT3.ResultsMore than 30% of the plant extracts at the concentration of 5 µg/ml showed strong inhibitory effect on the 6-CF uptake mediated by OAT1 (61 extracts) and OAT3 (55 extracts). Among them, three extracts for OAT1 and fourteen extracts for OAT3 were identified as strong inhibitors with IC50values being <5 µg/ml.Juncus effususshowed a strong inhibition to OAT3in vitro, and markedly altered thein vivopharmacokinetic parameters of furosemide in rats.ConclusionThe present study identified the potential interactions of medicinal and economic plants with human OAT1 and OAT3, which is helpful to predict and to avoid potential OAT1- and OAT3-mediated HDIs.

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Žlender, Vilim, Davorka Breljak, Marija Ljubojević, Dubravka Flajs, Daniela Balen, Hrvoje Brzica, Ana-Marija Domijan, Maja Peraica, Radovan Fuchs, and Naohiko Anzai. "Low doses of ochratoxin A upregulate the protein expression of organic anion transporters Oat1, Oat2, Oat3 and Oat5 in rat kidney cortex." Toxicology and Applied Pharmacology 239, no. 3 (September 15, 2009): 284–96. http://dx.doi.org/10.1016/j.taap.2009.06.008.

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Hagos, Yohannes, Gerhard Burckhardt, and Birgitta C. Burckhardt. "Human organic anion transporter OAT1 is not responsible for glutathione transport but mediates transport of glutamate derivatives." American Journal of Physiology-Renal Physiology 304, no. 4 (February 15, 2013): F403—F409. http://dx.doi.org/10.1152/ajprenal.00412.2012.

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Due to their clearance function, the kidneys are exposed to high concentrations of oxidants and potentially toxic substances. To maintain cellular integrity, renal cells have to be protected by sufficient concentrations of the antioxidant glutathione (GSH). We tested whether GSH or its precursors are taken up by human organic anion transporters 1 (OAT1) and 3 (OAT3) stably expressed in HEK293 cells. GSH did not inhibit uptake of p-aminohippurate (PAH) or of estrone sulfate (ES) in OAT3-transfected HEK293 cells. In OAT1-transfected cells, GSH reduced the uptake of PAH marginally. Among the GSH constituent amino acids, glutamate, cysteine, and glycine, only glutamate inhibited OAT1, but labeled glutamate was not taken up by a probenecid-inhibitable transport system. Thus OAT1 binds glutamate but is unable to translocate it. The GSH precursor dipeptide, cysteinyl glycine (cysgly), and the glutamate derivative N-acetyl glutamate (NAG), inhibited uptake of PAH when present in the medium and trans-stimulated uptake of PAH from the intracellular side, indicating that they are hitherto unrecognized transported substrates of OAT1. N-acetyl aspartate weakly interacted with OAT1, but aspartate did not. NAG inhibited also OAT3, albeit with much lower affinity compared with OAT1, and glutamate did not interact with OAT3 at all. Taken together, human OAT3 and OAT1 cannot be involved in renal GSH extraction from the blood. However, OAT1 could support intracellular GSH synthesis by taking up cysteinyl glycine.

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Ogasawara, Ken, Tomohiro Terada, Jun-ichi Asaka, Toshiya Katsura, and Ken-ichi Inui. "Hepatocyte nuclear factor-4α regulates the human organic anion transporter 1 gene in the kidney." American Journal of Physiology-Renal Physiology 292, no. 6 (June 2007): F1819—F1826. http://dx.doi.org/10.1152/ajprenal.00017.2007.

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Human organic anion transporter 1 (OAT1, SLC22A6), which is localized to the basolateral membranes of renal tubular epithelial cells, plays a critical role in the excretion of anionic compounds. OAT1 is regulated by various pathophysiological conditions, but little is known about the molecular mechanisms regulating the expression of OAT1. In the present study, we investigated the transcriptional regulation of OAT1 and found that hepatocyte nuclear factor (HNF)-4α markedly transactivated the OAT1 promoter. A deletion analysis of the OAT1 promoter suggested that the regions spanning −1191 to −700 base pairs (bp) and −140 to −79 bp were essential for the transactivation by HNF-4α. These regions contained a direct repeat separated by two nucleotides (DR-2), which is one of the consensus sequences binding to HNF-4α, and an inverted repeat separated by eight nucleotides (IR-8), which was recently identified as a novel element for HNF-4α, respectively. An electrophoretic mobility shift assay showed that HNF-4α bound to DR-2 and IR-8 under the conditions of HNF-4α overexpression. Furthermore, under normal conditions, HNF-4α bound to IR-8, and a mutation in IR-8 markedly reduced the OAT1 promoter activity, indicating that HNF-4α regulates the basal transcription of OAT1 via IR-8. This paper reports the first characterization of the human OAT1 promoter and the first gene in the kidney whose promoter activity is regulated by HNF-4α.

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TOJO, AKIHIRO, TAKASHI SEKINE, NORIKO NAKAJIMA, MAKOTO HOSOYAMADA, YOSHIKATSU KANAI, KENJIRO KIMURA, and HITOSHI ENDOU. "Immunohistochemical Localization of Multispecific Renal Organic Anion Transporter 1 in Rat Kidney." Journal of the American Society of Nephrology 10, no. 3 (March 1999): 464–71. http://dx.doi.org/10.1681/asn.v103464.

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Abstract. Renal proximal convoluted tubules have an important role, i.e., to excrete organic anions, including numerous drugs and endogenous substances. Recently, multispecific organic anion transporter 1 (OAT1) was isolated from rat kidney. In this study, the cellular and subcellular localization of OAT1 in rat kidney was investigated. Kidneys from normal rats were perfused and fixed with periodate-lysine-paraformaldehyde solution and were then processed for immunohistochemical analysis using the labeled streptavidin-biotin method, preembedding horseradish peroxidase method, and immunogold method. Light microscopic examination revealed immunostaining for OAT1 in the middle portion of the proximal tubule (S2 segment), but not in the initial portion of the proximal convoluted tubule, next to the glomerulus. Nephron segments other than the S2 segment and the renal vasculature were not stained with antibody to OAT1. Electron-microscopic observation using a preembedding method revealed that OAT1 was exclusively expressed in the basolateral membrane of S2 segments of proximal tubules. The immunogold method showed no labeling for OAT1 in the cytoplasmic vesicles, suggesting that OAT1 may not move together with organic anions into the cells. These results are consistent with previous physiologic data showing that organic anions, including para-aminohippurate, are taken up by the basolateral Na+-independent organic anion/dicarboxylate exchanger and excreted at S2 segments. In conclusion, OAT1 was localized to the basolateral membrane of S2 segments of proximal tubules in rat kidneys.

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Bukowska, Marta, Anna Bogacz, Marlena Wolek, Przemysław Ł. Mikołajczak, Piotr Olbromski, Adam Kamiński, and Bogusław Czerny. "Impact of Curcuma longa extract on the expression level of brain transporters in in vivo model." Herba Polonica 65, no. 1 (March 1, 2019): 32–39. http://dx.doi.org/10.2478/hepo-2019-0005.

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Summary Introduction: Blood brain barrier and multidrug resistance phenomenon are subjects of many investigations. Mainly, because of their functions in protecting the central nervous system (CNS) by blocking the delivery of toxic substances to the brain. This special function has some disadvantages, like drug delivery to the brain in neurodegenerative diseases Objective: The aim of this study was to examine how natural and synthetic substances affect the expression levels of genes (Mdr1a, Mdr1b, Mrp1, Mrp2, Oatp1a4, Oatp1a5 and Oatp1c1) that encode transporters in the blood-brain barrier. Methods: cDNA was synthesized from total RNA isolated from rat hippocampus. The expression level of genes was determined using real-time PCR (RT-PCR) method. Results: Our findings showed that verapamil, as a synthetic substance, caused the greatest reduction of mRNA level of genes studied. The standardized extract of Curcuma longa reduced the expression level for Mrp1 and Mrp2, whereas the increase of mRNA level was observed for Mdr1b, Oatp1a5 and Oatp1c1. Conclusions: These results suggests that herbal extracts may play an important role in overcoming the blood brain barrier during pharmacotherapy.

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Vallon, Volker, Timo Rieg, Sun Young Ahn, Wei Wu, Satish A. Eraly, and Sanjay K. Nigam. "Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics." American Journal of Physiology-Renal Physiology 294, no. 4 (April 2008): F867—F873. http://dx.doi.org/10.1152/ajprenal.00528.2007.

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Organic anion transporter (OAT) genes have been implicated in renal secretion of organic anions, but the individual in vivo contributions of OAT1 (first identified as NKT) and OAT3 remain unclear. Potential substrates include loop diuretics (e.g., furosemide) and thiazide diuretics (e.g., bendroflumethiazide), which reach their tubular sites of action mainly by proximal tubular secretion. Previous experiments in Oat1 knockout (−/−) mice revealed an almost complete loss of renal secretion of the prototypic organic anion p-aminohippurate (PAH) and a role of OAT1 in tubular secretion of furosemide (Eraly SA, Vallon V, Vaughn D, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK. J Biol Chem 281: 5072–5083, 2006). In this study we found that both furosemide and bendroflumethiazide inhibited mOat1- and mOat3-mediated uptake of a labeled tracer in Xenopus oocytes injected with cRNA, consistent with their being substrates for mouse OAT1 and OAT3. Experiments in Oat3−/− mice revealed intact renal secretion of PAH, but the dose-natriuresis curves for furosemide and bendroflumethiazide were shifted to the right and urinary furosemide excretion was impaired similar to the defect in Oat1−/− mice. Thus, whereas OAT1 (in contrast to OAT3) is the classic basolateral PAH transporter of the proximal tubule, both OAT1 and OAT3 contribute similarly to normal renal secretion of furosemide and bendroflumethiazide, and a lack of either one is not fully compensated by the other. Although microarray expression analysis in the kidneys of Oat1−/− and Oat3−/− mice revealed somewhat altered expression of a small number of transport-related genes, none were common to both knockout models. When searching for polymorphisms involved in human diuretic responsiveness, it may be necessary to consider both OAT1 and OAT3, among other genes.

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Vallon, Volker, Satish A. Eraly, Satish Ramachandra Rao, Maria Gerasimova, Michael Rose, Megha Nagle, Naohiko Anzai, et al. "A role for the organic anion transporter OAT3 in renal creatinine secretion in mice." American Journal of Physiology-Renal Physiology 302, no. 10 (May 15, 2012): F1293—F1299. http://dx.doi.org/10.1152/ajprenal.00013.2012.

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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.

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Wood, Charles E., Roderick Cousins, Daying Zhang, and Maureen Keller-Wood. "Ontogeny of Expression of Organic Anion Transporters 1 and 3 in Ovine Fetal and Neonatal Kidney." Experimental Biology and Medicine 230, no. 9 (October 2005): 668–73. http://dx.doi.org/10.1177/153537020523000909.

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Organic ions are excreted into the urine via the action of organic anion transporters (OATs). In adult kidney, both OAT1 and OAT3, both multispecific transporters, are abundant; OAT1 is a known transporter of para-aminohippurate (PAH) and OAT3 is a known transporter of sulfoconjugated estrogens. The present study was designed to test the hypotheses that the expression of both OAT1 and OAT3 are developmentally regulated and that the expression increases in late gestation. Fetal kidneys were collected at sacrifice of fetal sheep at 80, 100, 120, 130, and 145 days of gestation, as well as 1 day and 1 week after birth (n = 4–5 per group). Renal tissue was separated into cortex and medulla and snap-frozen in liquid nitrogen for later extraction of mRNA. The expression levels of OAT1 and OAT3 were measured using real-time reverse transcriptase polymerase chain reaction (RT-PCR), with specific probes and primers designed in our laboratory. Cellular distribution of protein expression was identified using immunohistochemistry with commercially available antisera. The OAT1 and OAT3 mRNA in renal cortex was increased in the more mature animals. At 145 days of gestation, OAT1 mRNA abundance was increased and remained elevated postnatally. Compared with prenatal ages, OAT3 mRNA was increased postnatally. The expression of both transporters was not significantly changed as a function of development in the renal medulla. The protein expression of OAT1 and OAT3 was identified in tubular epithelium in renal cortex, although the immunoreactivity for OAT1 was greater than for OAT3. We conclude that there is a developmental pattern of expression of both OAT1 and OAT3 in ovine renal cortex, and that the pattern of expression suggests that the function of both transporters is likely to be greater starting in late gestation.

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Kaufhold, Marcel, Katharina Schulz, Davorka Breljak, Shivangi Gupta, Maja Henjakovic, Wolfgang Krick, Yohannes Hagos, Ivan Sabolic, Birgitta C. Burckhardt, and Gerhard Burckhardt. "Differential interaction of dicarboxylates with human sodium-dicarboxylate cotransporter 3 and organic anion transporters 1 and 3." American Journal of Physiology-Renal Physiology 301, no. 5 (November 2011): F1026—F1034. http://dx.doi.org/10.1152/ajprenal.00169.2011.

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Organic anions are taken up from the blood into proximal tubule cells by organic anion transporters 1 and 3 (OAT1 and OAT3) in exchange for dicarboxylates. The released dicarboxylates are recycled by the sodium dicarboxylate cotransporter 3 (NaDC3). In this study, we tested the substrate specificities of human NaDC3, OAT1, and OAT3 to identify those dicarboxylates for which the three cooperating transporters have common high affinities. All transporters were stably expressed in HEK293 cells, and extracellularly added dicarboxylates were used as inhibitors of [14C]succinate (NaDC3), p-[3H]aminohippurate (OAT1), or [3H]estrone-3-sulfate (OAT3) uptake. Human NaDC3 was stably expressed as proven by immunochemical methods and by sodium-dependent uptake of succinate ( K0.5 for sodium activation, 44.6 mM; Hill coefficient, 2.1; Km for succinate, 18 μM). NaDC3 was best inhibited by succinate (IC50 25.5 μM) and less by α-ketoglutarate (IC50 69.2 μM) and fumarate (IC50 95.2 μM). Dicarboxylates with longer carbon backbones (adipate, pimelate, suberate) had low or no affinity for NaDC3. OAT1 exhibited the highest affinity for glutarate, α-ketoglutarate, and adipate (IC50 between 3.3 and 6.2 μM), followed by pimelate (18.6 μM) and suberate (19.3 μM). The affinity of OAT1 to succinate and fumarate was low. OAT3 showed the same dicarboxylate selectivity with ∼13-fold higher IC50 values compared with OAT1. The data 1) reveal α-ketoglutarate as a common high-affinity substrate of NaDC3, OAT1, and OAT3 and 2) suggest potentially similar molecular structures of the binding sites in OAT1 and OAT3 for dicarboxylates.

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Antonescu, Irina E., Maria Karlgren, Maria L. Pedersen, Ivailo Simoff, Christel A. S. Bergström, Sibylle Neuhoff, Per Artursson, Bente Steffansen, and Carsten Uhd Nielsen. "Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions." Pharmaceutics 12, no. 4 (April 24, 2020): 390. http://dx.doi.org/10.3390/pharmaceutics12040390.

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Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of SLC22A6) and OAT3 (gene product of SLC22A8) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with SLC22A6 or SLC22A8. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated p-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a Km-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a Ki-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3.

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Li, Caiyu, Xue Wang, Yajuan Bi, Heshui Yu, Jing Wei, Yi Zhang, Lifeng Han, and Youcai Zhang. "Potent Inhibitors of Organic Anion Transporters 1 and 3 From Natural Compounds and Their Protective Effect on Aristolochic Acid Nephropathy." Toxicological Sciences 175, no. 2 (May 3, 2020): 279–91. http://dx.doi.org/10.1093/toxsci/kfaa033.

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Abstract Organic anion transporters 1 and 3 (OAT1 and OAT3) play a critical role in renal drug-drug interactions and are involved in the nephrotoxicity of many anionic xenobiotics. To date, relatively little is known about the interaction of natural compounds with OAT1 and OAT3. Of the 270 natural compounds screened in the present study, 21 compounds inhibited OAT1 and 45 compounds inhibited OAT3. Further concentration-dependent studies identified 7 OAT1 inhibitors and 10 OAT3 inhibitors with IC50 values of <10 μM, and most of them were flavonoids, the most commonly ingested polyphenolic compounds in the diet and herbal products. Computational modeling of OAT1 and OAT3 revealed the important residues for the recognition of inhibitors. The two strong OAT inhibitors, namely wedelolactone and wogonin, were evaluated for their in vivo interactions with the OAT substrate aristolochic acid I (AAI), a natural compound causing aristolochic acid-induced nephropathy (AAN) in many species. The cytotoxicity of AAI increased in two OAT-overexpressing cell lines, with more cytotoxicity in OAT1-overexpressing cells, suggesting a more important role of OAT1 than OAT3 in AAN. Both wedelolactone and wogonin markedly increased serum AAI concentrations in AAI-treated rats and ameliorated kidney injuries in AAI-treated mice. To conclude, the present findings are of significant value in understanding natural compound-drug interactions and provide a natural source for developing treatments for AAN.

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Lin, Chang-Ching, Hsien-Yuan Fan, Chien-Wen Kuo, and Li-Heng Pao. "Evaluation of Chinese-Herbal-Medicine-Induced Herb-Drug Interactions: Focusing on Organic Anion Transporter 1." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–12. http://dx.doi.org/10.1155/2012/967182.

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The consumption of Chinese herbal medicines (CHMs) is increasing exponentially. Many patients utilize CHMs concomitantly with prescription drugs in great frequency. Herb-drug interaction has hence become an important focus of study. Transporter-mediated herb-drug interactions have the potential to seriously influence drug efficacy and toxicity. Since organic anion transporter 1 (OAT1) is crucial in renal active secretion and drug-drug interactions, the possibility of modulation of OAT1-mediated drug transport should be seriously concerned. Sixty-three clinically used CHMs were evaluated in the study. An hOAT1-overexpressing cell line was used for thein vitroCHMs screening, and the effective candidates were administered to Wistar rats to access renal hemodynamics. The regulation of OAT1 mRNA expression was also examined for further evidence of CHMs affecting OAT1-mediated transport. Among all the 63 CHMs, formulae Gui Zhi Fu Ling Wan (GZ) and Chia Wei Hsiao Yao San (CW) exhibited significant inhibitions on hOAT1-mediated [3H]-PAH uptakein vitroand PAH clearance and net secretionin vivo. Moreover, GZ showed concentration-dependent manners bothin vitroandin vivo, and the decrease of rOAT1 mRNA expression indicated that GZ not only inhibited function of OAT1 but also suppressed expression of OAT1.

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Jansen, Jitske, Katja Jansen, Ellen Neven, Ruben Poesen, Amr Othman, Alain van Mil, Joost Sluijter, et al. "Remote sensing and signaling in kidney proximal tubules stimulates gut microbiome-derived organic anion secretion." Proceedings of the National Academy of Sciences 116, no. 32 (July 24, 2019): 16105–10. http://dx.doi.org/10.1073/pnas.1821809116.

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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.

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Ljubojević, Marija, Carol M. Herak-Kramberger, Yohannes Hagos, Andrew Bahn, Hitoshi Endou, Gerhard Burckhardt, and Ivan Sabolić. "Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition." American Journal of Physiology-Renal Physiology 287, no. 1 (July 2004): F124—F138. http://dx.doi.org/10.1152/ajprenal.00029.2004.

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In rats, the secretion of p-aminohippurate (PAH) by the kidney is higher in males (M) than in females (F). The role of the major renal PAH transporters, OAT1 and OAT3, in the generation of these gender differences, as well as the responsible hormones and mechanisms, has not been clarified. Here we used various immunocytochemical methods to study effects of gender, gonadectomy, and treatment with sex hormones on localization and abundance of OAT1 and OAT3 along the rat nephron. Both transporters were localized to the basolateral membrane: OAT1 was strong in proximal tubule S2 and weak in the S3 segments, whereas OAT3 was stained in proximal tubule S1 and S2 segments, thick ascending limb, distal tubule, and in principal cells along the collecting duct. Gender differences in the expression of both transporters in adult rats (M > F) were observed only in the cortical tubules. OAT1 in the cortex was strongly reduced by castration in adult M, whereas the treatment of castrated M with testosterone, estradiol, or progesterone resulted in its complete restitution, further depression, or partial restitution, respectively. In adult F, ovariectomy weakly increased, whereas estradiol treatment of ovariectomized F strongly decreased, the expression of OAT1. The expression of OAT3 in the M and F cortex largely followed a similar pattern, except that ovariectomy and progesterone treatment showed no effect, whereas in other tissue zones gender differences were not observed. In prepubertal rats, the expression of OAT1 and OAT3 in the kidney cortex was low and showed no gender differences. Our data indicate that gender differences in the rat renal cortical OAT1 and OAT3 (M > F) appear after puberty and are determined by both a stimulatory effect of androgens (and progesterone in the case of OAT1) and an inhibitory effect of estrogens.

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Schneider, R., M. Meusel, B. Betz, C. Held, K. Möller-Ehrlich, M. Büttner-Herold, C. Wanner, M. Gekle, and C. Sauvant. "Oat1/3 restoration protects against renal damage after ischemic AKI." American Journal of Physiology-Renal Physiology 308, no. 3 (February 1, 2015): F198—F208. http://dx.doi.org/10.1152/ajprenal.00160.2014.

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Expression of proximal tubular organic anion transporters Oat1 and Oat3 is reduced by PGE2 after renal ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered probenecid, which blocks proximal tubular indomethacin uptake, to abolish the indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of ischemia. Probenecid (50 mg/kg) was administered ip 20 min later. Indomethacin restored the expression of Oat1/3, PAH net secretion, and PGE2 clearance. Additionally, indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and nitric oxide production. Notably, indomethacin did not affect inflammation parameters in the kidneys (e.g., monocyte chemoattractant protein-1, ED1+ cells). On the other hand, probenecid blocked the indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular indomethacin uptake abrogates the beneficial effect of indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.

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Hazelhoff, María Herminia, Romina Paula Bulacio, and Adriana Mónica Torres. "Organic Anion Transporter 5 Renal Expression and Urinary Excretion in Rats with Vascular Calcification." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/283429.

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It has been described renal damage in rats with vascular calcification. The organic anion transporter 5 (Oat5) is only expressed in kidney, and its urinary excretion was proposed as potential early biomarker of renal injury. The aim of this study was to evaluate the Oat5 renal expression and its urinary excretion in an experimental model of vascular calcification in comparison with traditional markers of renal injury. Vascular calcification was obtained by the administration of an overdose of vitamin D3(300,000 IU/kg, b.w., i.m.) to male Wistar rats. Oat5 urinary abundance was evaluated by Western blotting. Traditional markers of renal injury, such as creatinine and urea plasma levels, urinary protein levels, and urinary alkaline phosphatase (AP) activity, were determined using commercial kits. Histology was assessed by hematoxylin/eosin staining. Oat5 renal expression was evaluated by Western blotting and by immunohistochemistry. An increased expression of Oat5 in renal homogenates, in apical membranes, and in its urinary excretion was observed in rats with vascular calcification. The traditional parameters used to evaluate renal function were not modified, with the exception of histology. It is possible to postulate the urinary excretion of Oat5 as a potential noninvasive biomarker of renal injury associated with vascular calcification.

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Vriend, Jelle, Charlotte A. Hoogstraten, Kevin R. Venrooij, Bartholomeus T. van den Berge, Larissa P. Govers, Arno van Rooij, Marleen C. D. G. Huigen, et al. "Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells." Biological Chemistry 400, no. 10 (October 25, 2019): 1347–58. http://dx.doi.org/10.1515/hsz-2018-0446.

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Abstract Organic anion transporters (OATs) 1 and 3 are, besides being uptake transporters, key in several cellular metabolic pathways. The underlying mechanisms are largely unknown. Hence, we used human conditionally immortalized proximal tubule epithelial cells (ciPTEC) overexpressing OAT1 or OAT3 to gain insight into these mechanisms. In ciPTEC-OAT1 and -OAT3, extracellular lactate levels were decreased (by 77% and 71%, respectively), while intracellular ATP levels remained unchanged, suggesting a shift towards an oxidative phenotype upon OAT1 or OAT3 overexpression. This was confirmed by increased respiration of ciPTEC-OAT1 and -OAT3 (1.4-fold), a decreased sensitivity to respiratory inhibition, and characterized by a higher demand on mitochondrial oxidative capacity. In-depth profiling of tricarboxylic acid (TCA) cycle metabolites revealed reduced levels of intermediates converging into α-ketoglutarate in ciPTEC-OAT1 and -OAT3, which via 2-hydroxyglutarate metabolism explains the increased respiration. These interactions with TCA cycle metabolites were in agreement with metabolomic network modeling studies published earlier. Further studies using OAT or oxidative phosphorylation (OXPHOS) inhibitors confirmed our idea that OATs are responsible for increased use and synthesis of α-ketoglutarate. In conclusion, our results indicate an increased α-ketoglutarate efflux by OAT1 and OAT3, resulting in a metabolic shift towards an oxidative phenotype.

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Brandoni, Anabel, and Adriana M. Torres. "Altered Renal Expression of Relevant Clinical Drug Transporters in Different Models of Acute Uremia in Rats. Role of Urea Levels." Cellular Physiology and Biochemistry 36, no. 3 (2015): 907–16. http://dx.doi.org/10.1159/000430265.

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Background/Aims: Organic anion transporter 1 (Oat1) and 3 (Oat3) are organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. We investigated the effects of acute uremia on the renal expression of Oat1 and Oat3 in three in vivo experimental models of acute kidney injury (AKI): induced by ischemia, by ureteral obstruction and by the administration of HgCl2. We also evaluated the influence of urea in the expression of these transporters in proximal tubular cells suspensions. Methods: Membranes were isolated from kidneys of each experimental group and from cell suspensions incubated with different urea concentrations. Oat1 and Oat3 expressions were performed by immunoblotting. Results: A good correlation between uremia and the renal protein expression of Oat1 and Oat3 was observed in vivo. Moreover, the incubation of isolated proximal tubular cells with different concentrations of urea decreases protein expression of Oat1 and Oat3 in plasma membranes in a dose-dependent manner. Conclusion: The more severe the renal failure, the more important is the decrease in protein expression of the transporters in renal membranes where they are functional. The in vitro study demonstrates that urea accounts, at least in part, for the decreased expression of Oat1 and Oat3 in proximal tubule plasma membranes.

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Nakakariya, Masanori, Yoichiro Shima, Yoshiyuki Shirasaka, Keisuke Mitsuoka, Takeo Nakanishi, and Ikumi Tamai. "Organic anion transporter OAT1 is involved in renal handling of citrulline." American Journal of Physiology-Renal Physiology 297, no. 1 (July 2009): F71—F79. http://dx.doi.org/10.1152/ajprenal.90662.2008.

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Because citrulline plasma concentration is elevated in kidney failure, citrulline could be a biomarker of renal insufficiency, although the mechanism regulating its disposition in the kidney has not been clarified. In rat kidney slices, citrulline uptake was apparently Na+ dependent, saturable with Km 556 μM, and significantly inhibited by anionic (PAH) and cationic (TEA) compounds, but not by probenecid at 1 mM. Preincubation of kidney slices with glutarate increased citrulline uptake, while such an increase was not observed after preincubation of the slices in Na+-free buffer. This result suggested that a sodium-dependent dicarboxylate cotransporter is involved in citrulline uptake by rat kidney slices. In studies using transporter-overexpressing cells, human organic anion transporter 1 (OAT1) and rat Oat1 exhibited citrulline transport activity with Km values of 238 and 373 μM, respectively, while other OATs and organic cation transporters (OCTs) did not transport citrulline. Based on the relative activity factor method, the contribution of rat Oat1 to the overall uptake of citrulline in rat kidney slices was ∼70%. Moreover, the interaction among citrulline, PAH, and probenecid uptakes via rat Oat1 suggested that there are multiple functional sites on Oat1 and that the citrulline site may be distinct from the PAH and probenecid site. Thus OAT1/Oat1 appears to be one of the major contributors to renal basolateral uptake of citrulline, and impaired activities of these transporters may contribute substantially to the increase in plasma citrulline in renal failure. Accordingly, citrulline may be useful for diagnosis of kidney function as is creatinine.

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Jones, Carys S., David Sychantha, P. Lynne Howell, and Anthony J. Clarke. "Structural basis for the O-acetyltransferase function of the extracytoplasmic domain of OatA from Staphylococcus aureus." Journal of Biological Chemistry 295, no. 24 (April 29, 2020): 8204–13. http://dx.doi.org/10.1074/jbc.ra120.013108.

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Many bacteria possess enzymes that modify the essential cell-wall polymer peptidoglycan by O-acetylation. This modification occurs in numerous Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, a common cause of human infections. O-Acetylation of peptidoglycan protects bacteria from the lytic activity of lysozyme, a mammalian innate immune enzyme, and as such is important for bacterial virulence. The O-acetylating enzyme in Gram-positive bacteria, O-acetyltransferase A (OatA), is a two-domain protein consisting of an N-terminal integral membrane domain and a C-terminal extracytoplasmic domain. Here, we present the X-ray crystal structure at 1.71 Å resolution and the biochemical characterization of the C-terminal domain of S. aureus OatA. The structure revealed that this OatA domain adopts an SGNH-hydrolase fold and possesses a canonical catalytic triad. Site-specific replacement of active-site amino acids revealed the presence of a water-coordinating aspartate residue that limits esterase activity. This residue, although conserved in staphyloccocal OatA and most other homologs, is not present in the previously characterized streptococcal OatA. These results provide insights into the mechanism of acetyl transfer in the SGNH/GDSL hydrolase family and highlight important evolutionary differences between homologous OatA enzymes. Furthermore, this study enhances our understanding of PG O-acetyltransferases, which could guide the development of novel antibacterial drugs to combat infections with multidrug-resistant bacterial pathogens.

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Sugiura, Tomoko, Toru Otake, Takuya Shimizu, Tomohiko Wakayama, David L. Silver, Rie Utsumi, Tomohiro Nishimura, et al. "PDZK1 Regulates Organic Anion Transporting Polypeptide Oatpla in Mouse Small Intestine." Drug Metabolism and Pharmacokinetics 25, no. 6 (2010): 588–98. http://dx.doi.org/10.2133/dmpk.dmpk-10-rg-074.

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Towner, Justin, Brian Rago, David Rodrigues, Manoli Vourvahis, and Chris Holliman. "A novel hydrophilic interaction chromatography assay characterization of 4-pyridoxic acid, an emergent renal organic anion transporter 1/3 transporter biomarker." Bioanalysis 13, no. 18 (September 2021): 1391–400. http://dx.doi.org/10.4155/bio-2021-0110.

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Aim: 4-pyridoxic acid (PDA) has been proposed as an endogenous biomarker for renal organic anion transporter 1/3 (OAT1/3) inhibition. Clinical data are needed to support the proposal. Materials & methods: A hydrophilic interaction chromatography (HILIC)–LC/MS/MS assay was developed and characterized to support clinical drug–drug interaction (DDI) studies. Results: A HILIC–LC/MS/MS assay was successfully developed. PDA was measured in two clinical DDI studies; one where no significant OAT1/3 inhibition was observed and a second where a known inhibitor of the transporter was dosed. In both clinical studies, PDA plasma concentrations correlate to OAT1/3 function. Conclusion: The analysis of study samples from two clinical DDI studies using a HILIC–LC/MS/MS assay contributes further evidence that PDA is an endogenous biomarker for OAT1/3 inhibition.

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Schneider, R., C. Sauvant, B. Betz, M. Otremba, D. Fischer, H. Holzinger, C. Wanner, J. Galle, and M. Gekle. "Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats." American Journal of Physiology-Renal Physiology 292, no. 5 (May 2007): F1599—F1605. http://dx.doi.org/10.1152/ajprenal.00473.2006.

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Ischemic acute renal failure (iARF) was described to reduce renal extraction of the organic anion para-aminohippurate (PAH) in humans. The rate-limiting step of renal organic anion secretion is its basolateral uptake into proximal tubular cells. This process is mediated by the organic anion transporters OAT1 and OAT3, which both have a broad spectrum of substrates including a variety of pharmaceutics and toxins. Using a rat model of iARF, we investigated whether impairing the secretion of the organic anion PAH might be associated with downregulation of OAT1 or OAT3. Inulin and PAH clearance was determined starting from 6 up to 336 h after ischemia-reperfusion (I/R) injury. Net secretion of PAH was calculated and OAT1 as well as OAT3 expression was analyzed by RT-PCR and Western blotting. Inulin and PAH clearance along with PAH net secretion were initially diminished after I/R injury with a gradual recovery during follow-up. This initial impairment after iARF was accompanied by decreased mRNA and protein levels of OAT1 and OAT3 in clamped animals compared with sham-operated controls. In correlation to the improvement of kidney function, both mRNA and protein levels of OAT1 and OAT3 were upregulated during the follow-up. Thus decreased expression of OAT1 and OAT3 is sufficient to explain the decline of PAH secretion after iARF. As a result, this may have substantial impact on excretion kinetics and half-life of organic anions. As a consequence, the biological effects of a variety of organic anions may be affected after iARF.

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Henjakovic, Maja, Yohannes Hagos, Wolfgang Krick, Gerhard Burckhardt, and Birgitta C. Burckhardt. "Human organic anion transporter 2 is distinct from organic anion transporters 1 and 3 with respect to transport function." American Journal of Physiology-Renal Physiology 309, no. 10 (November 15, 2015): F843—F851. http://dx.doi.org/10.1152/ajprenal.00140.2015.

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Phylogentically, organic anion transporter (OAT)1 and OAT3 are closely related, whereas OAT2 is more distant. Experiments with human embryonic kidney-293 cells stably transfected with human OAT1, OAT2, or OAT3 were performed to compare selected transport properties. Common to OAT1, OAT2, and OAT3 is their ability to transport cGMP. OAT2 interacted with prostaglandins, and cGMP uptake was inhibited by PGE2 and PGF2α with IC50 values of 40.8 and 12.7 μM, respectively. OAT1 (IC50: 23.7 μM), OAT2 (IC50: 9.5 μM), and OAT3 (IC50: 1.6 μM) were potently inhibited by MK571, an established multidrug resistance protein inhibitor. OAT2-mediated cGMP uptake was not inhibited by short-chain monocarboxylates and, as opposed to OAT1 and OAT3, not by dicarboxylates. Consequently, OAT2 showed no cGMP/glutarate exchange. OAT1 and OAT3 exhibited a pH and a Cl− dependence with higher substrate uptake at acidic pH and lower substrate uptake in the absence of Cl−, respectively. Such pH and Cl− dependencies were not observed with OAT2. Depolarization of membrane potential by high K+ concentrations in the presence of the K+ ionophore valinomycin left cGMP uptake unaffected. In addition to cGMP, OAT2 transported urate and glutamate, but cGMP/glutamate exchange could not be demonstrated. These experiments suggest that OAT2-mediated cGMP uptake does not occur via exchange with monocarboxylates, dicarboxylates, and hydroxyl ions. The counter anion for electroneutral cGMP uptake remains to be identified.

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Mihaila, Silvia M., João Faria, Maurice F. J. Stefens, Dimitrios Stamatialis, Marianne C. Verhaar, Karin G. F. Gerritsen, and Rosalinde Masereeuw. "Drugs Commonly Applied to Kidney Patients May Compromise Renal Tubular Uremic Toxins Excretion." Toxins 12, no. 6 (June 12, 2020): 391. http://dx.doi.org/10.3390/toxins12060391.

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In chronic kidney disease (CKD), the secretion of uremic toxins is compromised leading to their accumulation in blood, which contributes to uremic complications, in particular cardiovascular disease. Organic anion transporters (OATs) are involved in the tubular secretion of protein-bound uremic toxins (PBUTs). However, OATs also handle a wide range of drugs, including those used for treatment of cardiovascular complications and their interaction with PBUTs is unknown. The aim of this study was to investigate the interaction between commonly prescribed drugs in CKD and endogenous PBUTs with respect to OAT1-mediated uptake. We exposed a unique conditionally immortalized proximal tubule cell line (ciPTEC) equipped with OAT1 to a panel of selected drugs, including angiotensin-converting enzyme inhibitors (ACEIs: captopril, enalaprilate, lisinopril), angiotensin receptor blockers (ARBs: losartan and valsartan), furosemide and statins (pravastatin and simvastatin), and evaluated the drug-interactions using an OAT1-mediated fluorescein assay. We show that selected ARBs and furosemide significantly reduced fluorescein uptake, with the highest potency for ARBs. This was exaggerated in presence of some PBUTs. Selected ACEIs and statins had either no or a slight effect at supratherapeutic concentrations on OAT1-mediated fluorescein uptake. In conclusion, we demonstrate that PBUTs may compete with co-administrated drugs commonly used in CKD management for renal OAT1 mediated secretion, thus potentially compromising the residual renal function.

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Iusuf, Dilek, Evita van de Steeg, and Alfred H. Schinkel. "Functions of OATP1A and 1B transporters in vivo: insights from mouse models." Trends in Pharmacological Sciences 33, no. 2 (February 2012): 100–108. http://dx.doi.org/10.1016/j.tips.2011.10.005.

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Yarim, Mine, Stefano Moro, Robert Huber, Peter J. Meier, Chosei Kaseda, Toru Kashima, Bruno Hagenbuch, and Gerd Folkers. "Application of QSAR analysis to organic anion transporting polypeptide 1a5 (Oatp1a5) substrates." Bioorganic & Medicinal Chemistry 13, no. 2 (January 2005): 463–71. http://dx.doi.org/10.1016/j.bmc.2004.10.009.

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Jin, Haibo, Bo Wang, Jiwei Hou, Tan Ma, Dan Qiao, Yingwen Miao, Jie Ding, and Xiaodong Han. "The mechanism of Oatp1a5-mediated microcystin-leucine arginine entering into GnRH neurons." Ecotoxicology and Environmental Safety 184 (November 2019): 109614. http://dx.doi.org/10.1016/j.ecoenv.2019.109614.

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Yu, Wen-Hao, Na Zhang, Jin-Feng Qi, Chen Sun, Yong-Hui Wang, and Mei Lin. "Arsenic and Mercury Containing Traditional Chinese Medicine (Realgar and Cinnabar) Strongly Inhibit Organic Anion Transporters, Oat1 and Oat3,In Vivoin Mice." BioMed Research International 2015 (2015): 1–7. http://dx.doi.org/10.1155/2015/863971.

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Toxic heavy metals, including mercury (Hg) and arsenic (As), accumulate preferentially in kidneys and always cause acute renal failure. The aim of this study was to investigate whether these samples affect organic anion transporters, Oat1 and Oat3,in vivoin mice kidney. Mice (n=10) were orally treated with investigational samples. After last administration, all mice were i.v.p-aminohippuric acid (PAH), and the blood and kidneys samples were collected. The concentrations of PAH were quantified by spectrophotometry. mRNA expressions of Oat1 and Oat3 were assayed by real-time PCR. In comparison with corresponding control, major pharmacokinetic parameters of PAH in sera were significantly changed by investigational samples (p<0.05), PAH accumulations in the kidney tissues were significantly higher (p<0.05), PAH uptake by renal slices was greatly reduced, Oat1 and Oat3 mRNA expression were significantly inhibited in investigational sample groups. Arsenic and mercury containing traditional Chinese medicine (Realgar and Cinnabar) probably induce kidney damage through inhibiting several members of the organic anion transporters (such as OAT1 and OAT3).

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Nigam, Anisha K., Julia G. Li, Kaustubh Lall, Da Shi, Kevin T. Bush, Vibha Bhatnagar, Ruben Abagyan, and Sanjay K. Nigam. "Unique metabolite preferences of the drug transporters OAT1 and OAT3 analyzed by machine learning." Journal of Biological Chemistry 295, no. 7 (January 2, 2020): 1829–42. http://dx.doi.org/10.1074/jbc.ra119.010729.

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The multispecific organic anion transporters, OAT1 (SLC22A6) and OAT3 (SLC22A8), the main kidney elimination pathways for many common drugs, are often considered to have largely-redundant roles. However, whereas examination of metabolomics data from Oat-knockout mice (Oat1 and Oat3KO) revealed considerable overlap, over a hundred metabolites were increased in the plasma of one or the other of these knockout mice. Many of these relatively unique metabolites are components of distinct biochemical and signaling pathways, including those involving amino acids, lipids, bile acids, and uremic toxins. Cheminformatics, together with a “logical” statistical and machine learning-based approach, identified a number of molecular features distinguishing these unique endogenous substrates. Compared with OAT1, OAT3 tends to interact with more complex substrates possessing more rings and chiral centers. An independent “brute force” approach, analyzing all possible combinations of molecular features, supported the logical approach. Together, the results suggest the potential molecular basis by which OAT1 and OAT3 modulate distinct metabolic and signaling pathways in vivo. As suggested by the Remote Sensing and Signaling Theory, the analysis provides a potential mechanism by which “multispecific” kidney proximal tubule transporters exert distinct physiological effects. Furthermore, a strong metabolite-based machine-learning classifier was able to successfully predict unique OAT1 versus OAT3 drugs; this suggests the feasibility of drug design based on knockout metabolomics of drug transporters. The approach can be applied to other SLC and ATP-binding cassette drug transporters to define their nonredundant physiological roles and for analyzing the potential impact of drug–metabolite interactions.

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Tahlan, Kapil, Hyeon Ung Park, Annie Wong, Perrin H. Beatty, and Susan E. Jensen. "Two Sets of Paralogous Genes Encode the Enzymes Involved in the Early Stages of Clavulanic Acid and Clavam Metabolite Biosynthesis in Streptomyces clavuligerus." Antimicrobial Agents and Chemotherapy 48, no. 3 (March 2004): 930–39. http://dx.doi.org/10.1128/aac.48.3.930-939.2004.

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ABSTRACT Recently, a second copy of a gene encoding proclavaminate amidinohydrolase (pah1), an enzyme involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus, was identified and isolated. Using Southern analysis, we have now isolated second copies of the genes encoding the carboxyethylarginine synthase (ceaS) and β-lactam synthetase (bls) enzymes. These new paralogues are given the gene designations ceaS1 and bls1 and are located immediately upstream of pah1 on the chromosome. Furthermore, sequence analysis of the region downstream of pah1 revealed a second copy of a gene encoding ornithine acetyltransferase (oat1), thus indicating the presence of a cluster of paralogue genes. ceaS1, bls1, and oat1 display 73, 60, and 63% identities, respectively, at the nucleotide level to the original ceaS2, bls2, and oat2 genes from the clavulanic acid gene cluster. Single mutants defective in ceaS1, bls1, or oat1 were prepared and characterized and were found to be affected to variable degrees in their ability to produce clavulanic acid and clavam metabolites. Double mutants defective in both copies of the genes were also prepared and tested. The ceaS1/ceaS2 and the bls1/bls2 mutant strains were completely blocked in clavulanic acid and clavam metabolite biosynthesis. On the other hand, oat1/oat2 double mutants still produced some clavulanic acid and clavam metabolites. This may be attributed to the presence of the argJ gene in S. clavuligerus, which encodes yet another ornithine acetyltransferase enzyme that may be able to compensate for the lack of OAT1 and -2 in the double mutants.

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Jones, Carys S., Alexander C. Anderson, and Anthony J. Clarke. "Mechanism of Staphylococcus aureus peptidoglycan O-acetyltransferase A as an O-acyltransferase." Proceedings of the National Academy of Sciences 118, no. 36 (September 3, 2021): e2103602118. http://dx.doi.org/10.1073/pnas.2103602118.

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The O-acetylation of exopolysaccharides, including the essential bacterial cell wall polymer peptidoglycan, confers resistance to their lysis by exogenous hydrolases. Like the enzymes catalyzing the O-acetylation of exopolysaccharides in the Golgi of animals and fungi, peptidoglycan O-acetyltransferase A (OatA) is predicted to be an integral membrane protein comprised of a membrane-spanning acyltransferase-3 (AT-3) domain and an extracytoplasmic domain; for OatA, these domains are located in the N- and C-terminal regions of the enzyme, respectively. The recombinant C-terminal domain (OatAC) has been characterized as an SGNH acetyltransferase, but nothing was known about the function of the N-terminal AT-3 domain (OatAN) or its homologs associated with other acyltransferases. We report herein the experimental determination of the topology of Staphylococcus aureus OatAN, which differs markedly from that predicted in silico. We present the biochemical characterization of OatAN as part of recombinant OatA and demonstrate that acetyl-CoA serves as the substrate for OatAN. Using in situ and in vitro assays, we characterized 35 engineered OatA variants which identified a catalytic triad of Tyr-His-Glu residues. We trapped an acetyl group from acetyl-CoA on the catalytic Tyr residue that is located on an extracytoplasmic loop of OatAN. Further enzymatic characterization revealed that O-acetyl-Tyr represents the substrate for OatAC. We propose a model for OatA action involving the translocation of acetyl groups from acetyl-CoA across the cytoplasmic membrane by OatAN and their subsequent intramolecular transfer to OatAC for the O-acetylation of peptidoglycan via the concerted action of catalytic Tyr and Ser residues.

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Schneider, R., M. Meusel, S. Renker, C. Bauer, H. Holzinger, M. Roeder, C. Wanner, M. Gekle, and C. Sauvant. "Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome." American Journal of Physiology-Renal Physiology 297, no. 6 (December 2009): F1614—F1621. http://dx.doi.org/10.1152/ajprenal.00268.2009.

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We have previously shown that expression of renal organic anion transporters Oat1 and Oat3 is diminished by prostaglandin E2 (PGE2) and that both transporters are downregulated after renal ischemia. Because PGE2 is increased after renal ischemia and is generated by cyclooxygenases (COX), we investigated the effect of the COX inhibitor indomethacin on expression of Oat1/3 after ischemic acute kidney injury (iAKI). iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. Indomethacin (1 mg/kg) was given intraperitoneally as soon as reperfusion started. Sham-treated animals served as controls. Oat1/3 were determined by qPCR and Western blot. PGE2 in blood and urine was measured by enzyme-linked immunosorbent assay. Invasion of monocytes/macrophages was determined. Glomerular filtration rate and renal plasma flow were determined. All parameters were detected 24 h after ischemia. PAH net secretion, as well as clearance and secretion of PGE2 were calculated. In clamped animals, indomethacin restored expression of Oat1/3, as well as PAH net secretion, PGE2 clearance, or PGE2 secretion. Additionally, indomethacin substantially improved kidney function as measured by glomerular filtration and PAH clearance. Indomethacin did not affect ischemia-induced invasion of monocytes/macrophages. In conclusion, our study indicates that low-dose indomethacin applied after ischemia prevents ischemia-induced downregulation of Oat1/3 during reperfusion and has a substantial protective effect on kidney function after iAKI. The beneficial effect of low-dose indomethacin on renal outcome is likely due to an effect different from inhibition of inflammation. In accordance to the decreased PAH net secretion, renal excretion of an endogenous organic anion (PGE2) is also impaired after ischemia and reperfusion.

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Neamatallah, Thikryat, Nagla El-Shitany, Aymn Abbas, Basma G. Eid, Steve Harakeh, Soad Ali, and Shaker Mousa. "Nano Ellagic Acid Counteracts Cisplatin-Induced Upregulation in OAT1 and OAT3: A Possible Nephroprotection Mechanism." Molecules 25, no. 13 (July 2, 2020): 3031. http://dx.doi.org/10.3390/molecules25133031.

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Cisplatin is an anticancer drug commonly used for solid tumors. However, it causes nephrotoxicity. OAT1 and OAT3 are organic anion transporters known to contribute to the uptake of cisplatin into renal tubular cells. The present study was designed to examine the protective role of ellagic acid nanoformulation (ellagic acid nano) on cisplatin-induced nephrotoxicity in rats, and the role of OAT1/OAT3 in this effect. Four groups of male Wistar rats were used (n = 6): (1) control, (2) cisplatin (7.5 mg/kg single dose, intraperitoneal), (3) cisplatin + ellagic acid nano (1 mg/kg), and (4) cisplatin + ellagic acid nano (2 mg/kg). Nephrotoxic rats treated with ellagic acid nano exhibited a significant reduction in elevated serum creatinine, urea, and oxidative stress marker, malondialdehyde (MDA). Additionally, ellagic acid nano restored renal glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Ellagic acid nano improved the histopathological changes induced by cisplatin, such as tubular dilatation, necrosis, and degeneration. Interestingly, OAT1 and OAT3 showed significantly lower expression at both mRNA and protein levels following ellagic acid nano treatment relative to the cisplatin-exposed group. These findings reveal a potential inhibitory role of ellagic acid antioxidant on OAT1 and OAT3 expression and thus explains its nephroprotective effect against cisplatin nephrotoxicity.

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Journal articles on the topic 'OAT15A'

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