title: Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers.
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).
authors.affiliation: 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.
authors.forename: Gleb
authors.initials: G
authors.lastname: Martovetsky
authors.affiliation: 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.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Bush
authors.affiliation: 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 snigam@ucsd.edu.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D000089762:Multidrug Resistance-Associated Protein 2; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D062725:Tight Junction Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D015415:Biomarkers; D000089762:Multidrug Resistance-Associated Protein 2; D027701:Organic Cation Transport Proteins; D062725:Tight Junction Proteins; D014157:Transcription Factors