Response of human renal tubular cells to cyclosporine and sirolimus: A toxicogenomic study

Journal Article · Sun Jun 01 00:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.01.019· OSTI ID:21140852

Pallet, Nicolas ^[1]; Rabant, Marion ^[1]; Xu-Dubois, Yi-Chun ^[2]; LeCorre, Delphine ^[1]; Mucchielli, Marie-Helene; Imbeaud, Sandrine; Agier, Nicolas ^[3]; Hertig, Alexandre ^[2]; Thervet, Eric; Legendre, Christophe ^[4]; Beaune, Philippe ^[1]; Anglicheau, Dany ^[1]

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1. INSERM U775, Universite Paris V, Centre Universitaire des Saints Peres, Paris (France)
2. INSERM U702, Universite Paris VI, Hopital Tenon, Paris (France)
3. Gif/Orsay DNA MicroArray Plateform (GODMAP), CNRS, Gif sur Yvette (France)
4. Service de Transplantation Renale, Hopital Necker, APHP, Paris (France)

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.

• OSTI ID: 21140852
• Journal Information: Toxicology and Applied Pharmacology, Vol. 229, Issue 2; Other Information: DOI: 10.1016/j.taap.2008.01.019; PII: S0041-008X(08)00025-2; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
BIOPSY
CELL MEMBRANES
CYCLOSPORINE
ENDOPLASMIC RETICULUM
IN VITRO
IN VIVO
KIDNEYS
OLIGONUCLEOTIDES
TRANSPLANTS