Cyclosporine A-induced apoptosis in renal tubular cells is related to oxidative damage and mitochondrial fission
Authors
Arriba De La Fuente, Gabriel De; Calvino Fernández, Mirian; Benito Martínez, Selma; Parra Cid, TrinidadIdentifiers
Permanent link (URI): http://hdl.handle.net/10017/59599DOI: 10.1016/j.toxlet.2013.01.007
ISSN: 0378-4274
Date
2013-06-21Affiliation
Universidad de Alcalá. Departamento de Medicina y Especialidades Médicas. Unidad Docente de MedicinaFunders
Junta de Comunidades de Castilla la Mancha
Instituto de Salud Carlos III
Bibliographic citation
Toxicology Letters, 2013, v. 218, n. 1, p. 30-38
Keywords
Cyclosporine
Reactive oxygen species
Mitochondrial fission
Mitochondrial fusion
Apoptosis
Description / Notes
22 p.
Project
info:eu-repo/grantAgreement/JCCM/Fiscam/PI-2006-02/ES//
info:eu-repo/grantAgreement/JCCM/Fiscam/MV2007JI%18/ES//
info:eu-repo/grantAgreement/ISCIII//CA07%00157/ES//
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/acceptedVersion
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
Cyclosporine A (CsA) nephrotoxicity has been linked to reactive oxygen species (ROS) production in renal cells. We have demonstrated that the antioxidant Vitamin E (Vit E) abolished renal toxicity in vivo and in vitro models. As one of the main sources of intracellular ROS are mitochondria, we studied the effects of CsA on several mitochondrial functions in LLC-PK1 cells. CsA induced ROS synthesis and decreased reduced glutathione (GSH). The drug decreased mitochondrial membrane potential (m) and induced physiological modifications in both the inner (IMM) and the outer mitochondrial membranes (OMM). In the IMM, CsA provoked mitochondrial permeability tran-sition pores (MPTP) and cytochrome c was liberated into the intermembrane space. CsA also induced pore formation in the OMM, allowing that intermembrane space contents can reach cytosol. Furthermore, CsA altered the mitochondrial dynamics, inducing an increase in mitochondrial fission; CsA increased the expression of dynamin related protein 1 (Drp1) that contributes to mitochondrial fission, and decreased the expression of mitofusin 2 (Mfn2) and optic atrophy protein 1 (Opa1), proteins involved in the fusion process. All these phenomena were related to apoptosis. These effects were inhibited when cells were treated with the antioxidant Vit E suggesting that they were mediated by the synthesis of ROS.
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