title: Response of human renal tubular cells to cyclosporine and sirolimus: a toxicogenomic study.
abstract: The molecular mechanisms involved in the potentially nephrotoxic response of tubular cells to immunosuppressive drugs remain poorly understood. Transcriptional profiles of human proximal tubular cells exposed to cyclosporine A (CsA), sirolimus (SRL) or their combination, were established using oligonucleotide microarrays. Hierarchical clustering of genes implicated in fibrotic processes showed a clear distinction between expression profiles with CsA and CsA+SRL treatments on the one hand and SRL treatment on the other. Functional analysis found that CsA and CsA+SRL treatments preferentially alter biological processes located at the cell membrane, such as ion transport or signal transduction, whereas SRL modifies biological processes within the nucleus and related to transcriptional activity. Genome wide expression analysis suggested that CsA may induce an endoplasmic reticulum (ER) stress in tubular cells in vitro. Moreover we found that CsA exposure in vivo is associated with the upregulation of the ER stress marker BIP in kidney transplant biopsies. In conclusion, this toxicogenomic study highlights the molecular interaction networks that may contribute to the tubular response to CsA and SRL. These results may also offer a new working hypothesis for future research in the field of CsA nephrotoxicity. Further studies are needed to evaluate if ER stress detection in tubular cells in human biopsies can predict CsA nephrotoxicity.
authors.affiliation: INSERM U775, Université Paris V, Centre Universitaire des Saints Pères, Paris, France. nicolas.pallet@univ-paris5.fr
authors.forename: Nicolas
authors.initials: N
authors.lastname: Pallet
authors.forename: Marion
authors.initials: M
authors.lastname: Rabant
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Xu-Dubois
authors.forename: Delphine
authors.initials: D
authors.lastname: Lecorre
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Mucchielli
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.forename: Nicolas
authors.initials: N
authors.lastname: Agier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Hertig
authors.forename: Eric
authors.initials: E
authors.lastname: Thervet
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Philippe
authors.initials: P
authors.lastname: Beaune
authors.forename: Dany
authors.initials: D
authors.lastname: Anglicheau
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity*; D017931:DNA Primers; D023281:Genomics; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D020123:Sirolimus / Q000633:toxicity*
chemical_list: D017931:DNA Primers; D016572:Cyclosporine; D020123:Sirolimus