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

Nigám, Sanjay K.; Wu, Wei; Bush, Kevin T.; Hoenig, Melanie P.; Blantz, Roland C.; Bhatnagar, Vibha

doi:10.2215/cjn.02440314

Cited by 228 publications

(216 citation statements)

References 115 publications

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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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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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“…There has recently been a call for more systematic analyses of the roles of these transporters, particularly the SLCs, in metabolism and signaling (1). There is also growing evidence showing relevance of OAT1 to metabolic disease, including chronic kidney disease (15,25,58). Taken together with the finding that these highly conserved drug transporters are differentially and highly expressed in various epithelial tissues lining body fluid compartments, it has been hypothesized that they potentially participate in remote communication ("remote sensing and signaling") between organs and organisms (2-4, 7, 9, 10, 27).…”

Section: Table 1 Top Pathways Affected By Oat1 Deficiency As Determinmentioning

confidence: 99%

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network

Liu

Jamshidi

Chen³

et al. 2016

Journal of Biological Chemistry

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There has been a recent interest in the broader physiological importance of multispecific "drug" transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wetlab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an "OAT1-centered metabolic interaction network." Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products, and socalled uremic toxins accumulating in chronic kidney disease. Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication: The Remote Sensing and Signaling Hypothesis (Nigam, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.A great deal of recent evidence suggests that solute carriers (SLC) 2 play a much broader role in physiology, including signaling and metabolism, than has been previously appreciated (1, 2). Indeed, there has been a recent call for more systematic analysis of the roles of SLCs in metabolism and signaling (1). Perhaps due to heavy emphasis on their key role in pharmacokinetics, members of the SLC (and ABC as well) "drug" transporter families are not generally depicted in biochemical pathways involving the endogenous metabolites they transport (2). Such an omission could have clinical consequences, because drugs directly or indirectly affect pathways normally involved in the movement of key metabolites, pathway intermediates, and signaling molecules, thereby fundamentally affecting cell and organ physiology in normal, pathophysiological, and developmental situations (1, 2). According to the remote sensing and signaling hypothesis, SLC and ABC drug transporters are important in regulating the movement of small endogenous molecules such as key metabolites (e.g. ␣-ketoglutarate, tryptophan metabolites), signaling molecules (e.g. cAMP, prostaglandins, polyamines), vitamins, antioxidant...

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“…A simulation study found that reducing the PTCPGK parameter in MechKiM by 15-fold was needed, in addition to changing GFR, to recover the observed AUC ratio between severe renal impairment and normal renal function subjects (39). However, other potential causes of reduced renal secretion include a downregulation of transporter expression, increased internalisation of renal drug transporters, and inhibition of transporters by uremic toxins that can accumulate in renal impairment (66)(67)(68). As accounting for reduced tubular secretion in a mechanistic manner is challenging, an alternative approach is to empirically estimate the extent that tubular secretion is reduced for several drugs, and apply this as a disease-specific scaling factor (69).…”

Section: Assessing Dosage Adjustment In Chronic Kidney Diseasementioning

confidence: 99%

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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Abstract.It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drugdrug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

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

Cited by 228 publications

References 115 publications

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

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

An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

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