title: Expression profiles of genes involved in xenobiotic metabolism and disposition in human renal tissues and renal cell models.
abstract: Numerous xenobiotics have been shown to be harmful for the kidney. Thus, to improve our knowledge of the cellular processing of these nephrotoxic compounds, we evaluated, by real-time PCR, the mRNA expression level of 377 genes encoding xenobiotic-metabolizing enzymes (XMEs), transporters, as well as nuclear receptors and transcription factors that coordinate their expression in eight normal human renal cortical tissues. Additionally, since several renal in vitro models are commonly used in pharmacological and toxicological studies, we investigated their metabolic capacities and compared them with those of renal tissues. The same set of genes was thus investigated in HEK293 and HK2 immortalized cell lines in commercial primary cultures of epithelial renal cells and in proximal tubular cell primary cultures. Altogether, our data offers a comprehensive description of kidney ability to process xenobiotics. Moreover, by hierarchical clustering, we observed large variations in gene expression profiles between renal cell lines and renal tissues. Primary cultures of proximal tubular epithelial cells exhibited the highest similarities with renal tissue in terms of transcript profiling. Moreover, compared to other renal cell models, Tacrolimus dose dependent toxic effects were lower in proximal tubular cell primary cultures that display the highest metabolism and disposition capacity. Therefore, primary cultures appear to be the most relevant in vitro model for investigating the metabolism and bioactivation of nephrotoxic compounds and for toxicological and pharmacological studies.
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Van der Hauwaert
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France.
authors.forename: Grégoire
authors.initials: G
authors.lastname: Savary
authors.affiliation: Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: David
authors.initials: D
authors.lastname: Buob
authors.affiliation: Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France; Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Leroy
authors.affiliation: Institut de Pathologie, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France; Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.affiliation: Service d'Urologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Flamand
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France; Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: Marie-Flore
authors.initials: MF
authors.lastname: Hennino
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR837, Centre de Recherche Jean-Pierre Aubert, Equipe 5, 59045 Lille, France.
authors.forename: Michaël
authors.initials: M
authors.lastname: Perrais
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lo-Guidice
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France. Electronic address: christelle.cauffiez@univ-lille2.fr.
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
authors.affiliation: EA4483, Université de Lille 2, Faculté de Médecine de Lille, Pôle Recherche, 59045 Lille, France; Service de Néphrologie, Hôpital Huriez, Centre Hospitalier Régional Universitaire de Lille, 59037 Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Glowacki
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects; D008954:Models, Biological; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016559:Tacrolimus / Q000633:toxicity; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D015262:Xenobiotics; D016559:Tacrolimus
keywords: Gene expression; In vitro models; Kidney; Xenobiotic processing