Quantitative proteomic analysis of cyclosporine-induced toxicity in a human kidney cell line and comparison with tacrolimus.

Fabien Lamoureux 1, 2 Elodie Mestre 1 Marie Essig 1, 3 François-Ludovic Sauvage 1, 2 Pierre Marquet 1, 2, * Louis Noël Gastinel 1
* Auteur correspondant
1 PIST - Pharmacologie des Immunosuppresseurs et de la Transplantation
2 Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges]
3 Service de Néphrologie, Dialyse, Transplantations [CHU Limoges]
Abstract : The calcineurin-inhibitors (CNIs) cyclosporine (CsA) and tacrolimus (TAC) remain the pillars of modern immunosuppression regimens used in solid organ transplantation. Nephrotoxicity is an adverse effect that limits their successful use. The precise molecular mechanisms underlying this nephrotoxicity remain unclear. Using SILAC together with LC-MALDI-TOF/TOF, we investigated the CNIs-induced proteomic perturbations in renal cells. Among the 495 proteins quantifiable in both forward and reverse SILAC, 69 displayed CsA-induced perturbations: proteins involved in ER-stress/protein folding, apoptosis, metabolism/transport or cytoskeleton pathways were up-regulated, while cyclophilin B as well as nuclear and RNA-processing proteins were down-regulated. Co-administration of CsA with the antioxidant N-acetylcysteine significantly decreased lipid peroxidation and also partially corrected the CsA-induced unfolded protein response. TAC toxicity profile was apparently different from that of CsA, especially without perturbation of cyclophilins A and B, up-regulation of ER-chaperones nor down-regulation of a number of nuclear proteins. These results provide a new insight and are consistent with recent data regarding the molecular mechanisms of CNIs-induced nephrotoxicity. Our findings offer new directions for future research aiming to identify specific biomarkers of CsA nephrotoxicity.
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Journal of Proteomics, Elsevier, 2011, 75 (2), pp.677-94. 〈10.1016/j.jprot.2011.09.005〉
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Contributeur : Pierre Marquet <>
Soumis le : mercredi 8 janvier 2014 - 11:27:54
Dernière modification le : vendredi 16 février 2018 - 15:24:59

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Fabien Lamoureux, Elodie Mestre, Marie Essig, François-Ludovic Sauvage, Pierre Marquet, et al.. Quantitative proteomic analysis of cyclosporine-induced toxicity in a human kidney cell line and comparison with tacrolimus.. Journal of Proteomics, Elsevier, 2011, 75 (2), pp.677-94. 〈10.1016/j.jprot.2011.09.005〉. 〈inserm-00925562〉

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