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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

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

Gleb Martovetsky, Kevin T. Bush and Sanjay K. Nigam
Drug Metabolism and Disposition July 2016, 44 (7) 1050-1060; DOI: https://doi.org/10.1124/dmd.115.068254
Gleb Martovetsky
Department of Pediatrics (G.M., K.T.B., S.K.N.), Department of Medicine, Division of Nephrology and Hypertension, (S.K.N.), and Department of Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California
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Kevin T. Bush
Department of Pediatrics (G.M., K.T.B., S.K.N.), Department of Medicine, Division of Nephrology and Hypertension, (S.K.N.), and Department of Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California
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Sanjay K. Nigam
Department of Pediatrics (G.M., K.T.B., S.K.N.), Department of Medicine, Division of Nephrology and Hypertension, (S.K.N.), and Department of Cellular and Molecular Medicine (S.K.N.), University of California, San Diego, La Jolla, California
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Abstract

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).

Footnotes

    • Received November 6, 2015.
    • Accepted March 30, 2016.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants GM098449 and GM104098], the National Institutes of Health National Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant U54 HD07160], and the Nancy Kaehr Chair in Research at the University of California, San Diego.

  • dx.doi.org/10.1124/dmd.115.068254.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (7)
Drug Metabolism and Disposition
Vol. 44, Issue 7
1 Jul 2016
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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Hnf1a/Hnf4a Modulation of Kidney versus Liver Specification

Gleb Martovetsky, Kevin T. Bush and Sanjay K. Nigam
Drug Metabolism and Disposition July 1, 2016, 44 (7) 1050-1060; DOI: https://doi.org/10.1124/dmd.115.068254

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Research ArticleSpecial Section on Pediatric Drug Disposition and Pharmacokinetics

Hnf1a/Hnf4a Modulation of Kidney versus Liver Specification

Gleb Martovetsky, Kevin T. Bush and Sanjay K. Nigam
Drug Metabolism and Disposition July 1, 2016, 44 (7) 1050-1060; DOI: https://doi.org/10.1124/dmd.115.068254
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