کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1225632 | 968239 | 2012 | 14 صفحه PDF | دانلود رایگان |
Nephrotoxicity is an adverse event that strongly limits the use of the immunosuppressant cyclosporine in solid organ transplantation and the precise molecular mechanisms underlying this toxicity remain unclear. MS-based proteomic analysis of the secretome of HEK-293 renal cells exposed to cyclosporine was performed to identify changes in protein secretion, as a first step to discover potential biomarkers of such nephrotoxicity. To detect and quantify the perturbed proteins in the culture medium we used SILAC and nano-scale liquid chromatography followed by MALDI-TOF/TOF mass spectrometry. Among 106 proteins identified, 80 were quantified in both forward/reverse SILAC experiments and quantitative proteomic analysis revealed altered levels of expression for 24 secreted proteins. These included the down-regulation of a number of extracellular matrix/cell adhesion components, and the up-regulation of secreted cyclophilins A and B, macrophage inhibition factor and phosphatidylethanolamine-binding protein 1. These changes in protein secretion were not prevented by co-incubation with the antioxidant N-acetylcysteine, suggesting that they were not triggered by cyclosporine-induced oxidative stress. The results from the present study provide important new knowledge to gain insights into the molecular mechanisms of cyclosporine-related toxicity. Some of the proteins identified here should be tested as potential biomarkers of cyclosporine nephrotoxicity in subsequent clinical studies.
Figure optionsDownload high-quality image (152 K)Download as PowerPoint slideHighlights
► Nephrotoxicity is an adverse effect that limits the use of cyclosporine (CsA) in solid organ transplantation.
► Using SILAC we studied CsA-induced changes in secreted protein expression of human renal cells.
► CsA induced altered secretion of 24 proteins, including a dramatical increase in secreted cyclophilins A and B.
► These changes in protein secretion were not corrected by co-administration of N-acetylcysteine.
► This work raises new directions for future research about CsA nephrotoxicity.
Journal: Journal of Proteomics - Volume 75, Issue 12, 27 June 2012, Pages 3674–3687