Evolutionary Analysis and Classification of OATs, OCTs, OCTNs, and Other SLC22 Transporters: Structure-Function Implications and Analysis of Sequence Motifs

Zhu, Christopher; Nigam, Kabir B.; Date, Rishabh C.; Bush, Kevin T.; Springer, Stevan A.; Saier, Milton H.; Wu, Wei; Nigám, Sanjay K.

doi:10.1371/journal.pone.0140569

Cited by 80 publications

(105 citation statements)

References 55 publications

(94 reference statements)

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“…While the discussion here has tended to focus more on renal drug transporters of the SLC22 family (especially OAT1 and OAT3), it is important to emphasize that many of the same principles and considerations are likely to apply to other SLC and ABC drug transporters in the kidney. Moreover, by focusing on the differences in tissue expression patterns, substrate specificities, regulation in development, evolutionary biology, and disease states, the field is just beginning to understand the role these drug transporters play not only in drug and toxin handling but in normal physiology and pathophysiology (24,65,69,112,113). Viewing uremia partly as a disorder of remote sensing and signaling may lead to new avenues of research and, possibly, novel therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

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229

192

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The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

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Section: Discussionmentioning

confidence: 99%

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Nigám¹,

Wu²,

Bush³

et al. 2015

Clinical Journal of the American Society of Nephrology

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229

192

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“…This requires establishment of a permeability barrier (mediated by tight junctions), expression of appropriate ABC and SLC drug and solute transporters, as well as drug-metabolizing enzymes. For example, the major transporter of many organic anion drugs, toxins, and metabolites, OAT1 (originally identified as NKT) must be expressed on the basolateral surface of the proximal tubule cell (Lopez-Nieto et al, 1997;Nigam et al, 2015b;Wu et al, 2015;Zhu et al, 2015); when this gene is deleted, there is considerable loss of renal transport of many organic anion drugs, toxins, and metabolites (Eraly et al, 2006;Truong et al, 2008;Nagle et al, 2011;Torres et al, 2011;Wikoff et al, 2011). Although there is some commonality of expressed genes, they are often differentially expressed.…”

Section: Discussionmentioning

confidence: 99%

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

Martovetsky

Bush

Nigám

2016

Drug Metabolism and Disposition

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The hepatocyte nuclear factors, Hnf1a and Hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineage-determining transcription factors in the kidney proximal tubule (PT) [Martovetsky et. al., (2012) Mol Pharmacol 84:808], implying an additional level of regulation that is potentially important in developmental and/or tissue-engineering contexts. Mouse embryonic fibroblasts (MEFs) transduced with Hnf1a and Hnf4a form tight junctions and express multiple PT drug transporters (e.g., Slc22a6/Oat1, Slc47a1/Mate1, Slc22a12/Urat1, Abcg2/Bcrp, Abcc2/Mrp2, Abcc4/Mrp4), nutrient transporters (e.g., Slc34a1/NaPi-2, Slco1a6), and tight junction proteins (occludin, claudin 6, ZO-1/Tjp1, ZO-2/Tjp2). In contrast, the coexpression (with Hnf1a and Hnf4a) of GATA binding protein 4 (Gata4), as well as the forkhead box transcription factors, Foxa2 and Foxa3, in MEFs not only downregulates PT markers but also leads to upregulation of several hepatocyte markers, including albumin, apolipoprotein, and transferrin. A similar result was obtained with primary mouse PT cells. Thus, the presence of Gata4 and Foxa2/Foxa3 appears to alter the effect of Hnf1a and Hnf4a by an as-yet unidentified mechanism, leading toward the generation of more hepatocyte-like cells as opposed to cells exhibiting PT characteristics. The different roles of Hnf4a in the kidney and liver was further supported by reanalysis of ChIP-seq data, which revealed Hnf4a colocalization in the kidney near PT-enriched genes compared with those genes enriched in the liver. These findings provide valuable insight, not only into the developmental, and perhaps organotypic, regulation of drug transporters, drug-metabolizing enzymes, and tight junctions, but also for regenerative medicine strategies aimed at restoring the function of the liver and/or kidney (acute kidney injury, AKI; chronic kidney disease, CKD).

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“…The gene has been found to be mutated in certain Japanese patients with hypouricemia and exercise-induced uric acid stones [40]. It is important to remember, however, that URAT1 is a member of the OAT major clade of the SLC22 family and closely related to OAT1, OAT3, and OAT6 [41]. Although much more limited in specificity than OAT1 and OAT3, and with a strong preference for urate, URAT1 nonetheless binds a few molecules other than urate.…”

Section: Mechanisms Of Uric Acid Handling and The ‘Remote Sensing Andmentioning

confidence: 99%

“…OAT1 (SLC22A6) and OAT3 (SLC22A8) are, like URAT1 (SLC22A12), members of the OAT major clade of the SLC22 transporter family [19*,41]. Indeed, they are among the best known members of this family because, like ABCG2, they are widely regarded as among the major multispecific ‘drug’ transporters of the body [18].…”

Section: Mechanisms Of Uric Acid Handling and The ‘Remote Sensing Andmentioning

confidence: 99%

The systems biology of uric acid transporters

Nigám¹,

Bhatnagar

2018

Current Opinion in Nephrology and Hypertension

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Purpose of review Uric acid homeostasis in the body is mediated by a number of SLC and ABC transporters in the kidney and intestine, including several multispecific ‘drug’ transporters (e.g., OAT1, OAT3, and ABCG2). Optimization of uric acid levels can be viewed as a ‘systems biology’ problem. Here, we consider uric acid transporters from a systems physiology perspective using the framework of the ‘Remote Sensing and Signaling Hypothesis.’ This hypothesis explains how SLC and ABC ‘drug’ and other transporters mediate interorgan and interorganismal communication (e.g., gut microbiome and host) via small molecules (e.g., metabolites, antioxidants signaling molecules) through transporters expressed in tissues lining body fluid compartments (e.g., blood, urine, cerebrospinal fluid). Recent findings The list of uric acid transporters includes: SLC2A9, ABCG2, URAT1 (SLC22A12), OAT1 (SLC22A6), OAT3 (SLC22A8), OAT4 (SLC22A11), OAT10 (SLC22A13), NPT1 (SLC17A1), NPT4 (SLC17A3), MRP2 (ABCC2), MRP4 (ABCC4). Normally, SLC2A9, – along with URAT1, OAT1 and OAT3, – appear to be the main transporters regulating renal urate handling, while ABCG2 appears to regulate intestinal transport. In chronic kidney disease (CKD), intestinal ABCG2 becomes much more important, suggesting remote organ communication between the injured kidney and the intestine. Summary The remote sensing and signaling hypothesis provides a useful systems-level framework for understanding the complex interplay of uric acid transporters expressed in different tissues involved in optimizing uric acid levels under normal and diseased (e.g., CKD, gut microflora dysbiosis) conditions.

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Evolutionary Analysis and Classification of OATs, OCTs, OCTNs, and Other SLC22 Transporters: Structure-Function Implications and Analysis of Sequence Motifs

Cited by 80 publications

References 55 publications

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Handling of Drugs, Metabolites, and Uremic Toxins by Kidney Proximal Tubule Drug Transporters

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

The systems biology of uric acid transporters

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