Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death.
Calcineurin inhibitors cyclosporine and tacrolimus are effective immunosuppressants, but both substances have the same intrinsic nephrotoxic potential that adversely affects allograft survival in renal transplant patients and causes end-stage renal disease in other solid organ or bone marrow transplant recipients. Endothelial cells are the first biological interface between drugs and the kidney, and calcineurin inhibitors may influence endothelial function and viability in a number of ways. Notably, endothelial cells have recently been shown to contribute to the accumulation of interstitial fibroblasts in nonrenal models, through endothelial-to-mesenchymal transition. Here we demonstrate that cyclosporine, but not tacrolimus or its metabolites, induces morphological and phenotypic endothelial changes suggestive of a partial endothelial-to-mesenchymal transition in human umbilical arterial endothelial cells. We identify for the first time a contingent of interstitial myofibroblasts that coexpress endothelial markers in rat kidneys treated with cyclosporine, suggesting that endothelial-to-mesenchymal transition could occur in vivo. Finally, our findings suggest that endoplasmic reticulum stress triggered by cyclosporine induces endothelial cells to undergo endothelial phenotypic changes suggestive of a partial endothelial-to-mesenchymal transition, whereas salubrinal partially preserves the endothelial phenotype. Inversely, tacrolimus does not induce endothelial-to-mesenchymal transition or endoplasmic reticulum stress. In conclusion, this study demonstrates for the first time that cyclosporine, and not tacrolimus, induces endoplasmic reticulum stress in endothelial cells. Our findings also suggest that endoplasmic reticulum stress contributes to endothelial cell death and phenotypic changes similar to a partial endothelial-to-mesenchymal transition.
Bouvier
Nicolas
N
Unité INSERM U775, Centre Universitaire des Saints Pères, 45, rue des saints Pères, 75006 Paris, France. nicolas.pallet@univ-paris5.fr
Flinois
Jean Pierre
JP
Gilleron
Jerome
J
Sauvage
François-Ludovic
FL
Legendre
Christophe
C
Beaune
Philippe
P
Thervet
Eric
E
Anglicheau
Dany
D
Pallet
Nicolas
N
D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008648:Mesoderm / Q000473:pathology; D010641:Phenotype; D016559:Tacrolimus / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014469:Umbilical Arteries / Q000187:drug effects / Q000473:pathology
D002934:Cinnamates; D007166:Immunosuppressive Agents; C496827:salubrinal; D016572:Cyclosporine; D013890:Thiourea; D016559:Tacrolimus