The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

Sager, Georg; Smaglyukova, Natalia; Fuskevaag, Ole-Martin

doi:10.1002/jcp.26409

Cited by 12 publications

(16 citation statements)

References 55 publications

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“…An additional consideration is that the blood‐to‐plasma concentration ratio of 1 was assumed in the model due to lack of supporting data. Creatinine is OAT2 substrate (expressed in red blood cells), and showed saturable uptake into human red blood cells 47 . Given the scarcity of measured f u,p and blood‐to‐plasma ratio data, and their importance in the models, measurements using modern techniques would be beneficial.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Scotcher

Arya

Yang

et al. 2020

CPT Pharmacom & Syst Pharma

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Creatinine is widely used as a biomarker of glomerular filtration, and, hence, renal function. However, transporter-mediated secretion also contributes to its renal clearance, albeit to a lesser degree. Inhibition of these transporters causes transient serum creatinine elevation, which can be mistaken as impaired renal function. The current study developed mechanistic models of creatinine kinetics within physiologically based framework accounting for multiple transporters involved in creatinine renal elimination, assuming either unidirectional or bidirectional-OCT2 transport (driven by electrochemical gradient). Robustness of creatinine models was assessed by predicting creatinine-drug interactions with 10 perpetrators; performance evaluation accounted for 5% intra-individual variability in serum creatinine. Models showed comparable predictive performances of the maximum steady-state effect regardless of OCT2 directionality assumptions. However, only the bidirectional-OCT2 model successfully predicted the minimal effect of ranitidine. The dynamic nature of models provides clear advantage to static approaches and most advanced framework for evaluating interplay between multiple processes in creatinine renal disposition.

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Section: Discussionmentioning

confidence: 99%

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Scotcher

Arya

Yang

et al. 2020

CPT Pharmacom & Syst Pharma

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“…Here, we describe that the IS effects on ROS production and PS exposure by erythrocytes were abrogated by the presence of a specific inhibitor for organic anion transporter 2 (OAT2), suggesting internalization as a mechanism for IS uremic toxicity to RBCs. Sager et al [ 15 ] described not only the OAT2 expression on RBC surface, but also its activity with the uptake of organic anions, such as cyclic nucleotides, creatinine, and indomethacin. OAT2 is a member of the SLC family (SLC22) that mediates the uptake of organic ions and it is associated to renal clearance of several drugs [ 20 , 21 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…OAT1 and OAT3 have previously been shown to interact with many of uremic toxins in vitro and some in vivo data indicate that the OATs also handle many endogenous metabolites [ 12 , 13 , 14 ]. Recently, Sager and collaborators [ 15 ] characterized the transporters that are responsible for the uptake of cyclic nucleotides to human RBC surface and by western blotting, showing an expression of OAT2, but no expression of OAT1 or OAT3. Human-OAT2 was observed at the basolateral side of the proximal tubule, where it mediates the transport of organic anions, including salicylate and prostaglandin F2a, as well as interacting with IS [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways

Dias

Bonan

Steiner

et al. 2018

Toxins

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It is hypothesized that the uremic toxin indoxyl sulfate (IS) plays a role in the pathogenesis of renal anemia. To further explore that hypothesis, we examined the effects of IS on reactive oxygen species (ROS) production, levels of reduced glutathione (GSH), and erythrocyte death (eryptosis) in red blood cells (RBC) from healthy controls (CON-RBC) and hemodialyzed patients (HD-RBC), respectively. RBC were incubated either in either TRIS-Glc-BSA buffer or IS at concentrations of 0.01, 0.09, and 0.17 mM, respectively. We measured ROS generation (expressed as % of DCFH-DA positive RBC), eryptosis (expressed as % of annexin-V positive RBC), and GSH levels after 6, 12, and 24 h. When incubated in buffer, ROS production was approximately seven-fold higher at all time points HD-RBC when compared to CON-RBC. Incubation with IS increased ROS production in CON-RBS dose-dependently up to 10-fold. Eryptosis in buffer-incubated HD-RBC was up to seven-fold higher as compared to COB-RBC. Incubation of CON-RBC with IS increased the eryptosis rate dose-dependently up to 6-fold. Pretreatment of CON-RBC with the organic anion transporter 2 (OAT2) specific inhibitor ketoprofen or with NADPH oxidase inhibitor diphenyleneiodonium-Cl blunted the IS effect on both ROS production and eryptosis induction. While GSH levels in HD-RBC were reduced when compared to CON-RBC, they were not affected by IS incubation. In summary, IS increases ROS generation and eryptosis in CON-RBC by an activity dependent of the IS influx through OAT2, and NADPH oxidase activity-dependent, and a GSH-independent mechanism. These findings lend support to a putative role of IS in the pathogenesis of renal anemia.

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“…Another distinguishing feature of OAT2 is its tissue expression patterns ( Table 4). While its expression in the liver and kidney are common to many SLC22 members, it has been localized to circulating red blood cells, where it may function in cyclic nucleotide transport (3). Its expression in a mobile cell type and transport of cyclic nucleotides raises the possibility that it may act as an avenue for signaling.…”

Section: Oats2 (Slc22a7) Is a Systemically-expressed Transporter Of Omentioning

confidence: 99%

“…SLC22A7), monocytes, and macrophages (e.g. SLC22A3, SLC22A4, SLC22A15, and SLC22A16) (3,4). With recent calls for research on solute carriers, there has been a large influx of data over the past five years, including novel roles in remote sensing and signaling, leading to the need for a more comprehensive understanding of the functional importance of transporters (5).…”

Section: Introductionmentioning

confidence: 99%

Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups

Engelhart

Granados

Nigám

et al. 2019

Preprint

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AbstractAmong transporters, the SLC22 family is emerging as a central hub of endogenous physiology. The family consists of organic anion transporters (OATs), organic cation transporters (OCTs) and zwitterion transporters (OCTNs). Despite being known as “drug” transporters, these multi-specific, oligo-specific, and relatively mono-specific transporters facilitate the movement of metabolites and key signaling molecules. An in-depth reanalysis supports a reassignment of these proteins into eight functional subgroups with four new subgroups arising from the previously defined OAT subclade. These OAT subgroups are: OATS1 (SLC22A6, SLC22A8, and SLC22A20), OATS2 (SLC22A7), OATS3 (SLC22A11, SLC22A12, and Slc22a22), and OATS4 (SLC22A9, SLC22A10, SLC22A24, and SLC22A25). We propose merging the OCTN (SLC22A4, SLC22A5, and Slc22a21) and OCT-related (SLC22A15 and SLC22A16) subclades into the OCTN/OCTN-related subgroup. Functional support for the eight subgroups comes from network analysis of data from GWAS, in vivo models, and in vitro assays. These data emphasize shared substrate specificity of SLC22 transporters for characteristic metabolites such as prostaglandins, uric acid, carnitine, creatinine, and estrone sulfate. Some important subgroup associations include: OATS1 with metabolites, signaling molecules, uremic toxins and odorants, OATS2 with cyclic nucleotides, OATS3 with uric acid, OATS4 with conjugated sex hormones, particularly etiocholanolone glucuronide, OCT with monoamine neurotransmitters, and OCTN/OCTN-related with ergothioneine and carnitine derivatives. The OAT-like and OAT-related subgroups remain understudied and therefore do not have assigned functionality. Relatedness within subgroups is supported by multiple sequence alignments, evolutionarily conserved protein motifs, genomic localization, and tissue expression. We also highlight low level sequence similarity of SLC22 members with other non-transport proteins. Our data suggest that the SLC22 family can work among itself, as well as with other transporters and enzymes, to optimize levels of numerous metabolites and signaling molecules, as proposed by the Remote Sensing and Signaling Theory.

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The role of OAT2 (SLC22A7) in the cyclic nucleotide biokinetics of human erythrocytes

Cited by 12 publications

References 55 publications

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Mechanistic Models as Framework for Understanding Biomarker Disposition: Prediction of Creatinine‐Drug Interactions

Indoxyl Sulfate, a Uremic Toxin, Stimulates Reactive Oxygen Species Production and Erythrocyte Cell Death Supposedly by an Organic Anion Transporter 2 (OAT2) and NADPH Oxidase Activity-Dependent Pathways

Reclassification of SLC22 Transporters: Analysis of OAT, OCT, OCTN, and other Family Members Reveals 8 Functional Subgroups

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