title: Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling.
abstract: Cyclosporine A (CsA) is a potent immunosuppressant used to prevent organ transplant rejection and in the treatment of autoimmune diseases. However, chronic CsA nephropathy is the major limiting factor to its widespread use. The exact mechanisms of CsA-induced renal damage remain to be fully elucidated. The objective of the current research was to examine whether CsA treatment induced any glomerular mesangial cell alterations. In this research goal, human mesangial cells (HMCs) were treated with CsA for various time points. CsA caused an increase in the production of reactive oxygen species (ROS). Microarray analysis of mesangial cells treated with CsA also indicated 282 dysregulated genes. Bioinformatic analysis of these 282 genes indicated enriched apoptotic oxidative stress, mitogen-activated protein kinase (MAPK), and transforming growth factor-β signaling in response to CsA treatment. The focus of this study was directed on oxidative stress and MAPK signaling as potential novel mechanisms of CsA nephrotoxicity. One key contributor to oxidative stress, thioredoxin interacting protein, was significantly upregulated following CsA treatment. Inhibition of the MAPK pathway resulted in attenuation of the CsA-induced mesangial cell alterations. These findings suggest a major role for ROS, oxidative stress, and MAPK signaling in promoting CsA-induced glomerular dysfunction and subsequent nephrotoxicity.
authors.affiliation: UCD School of Biomolecular and Biomedical Research, UCD Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: Séin
authors.initials: S
authors.lastname: O'Connell
authors.forename: Niamh
authors.initials: N
authors.lastname: Tuite
authors.forename: Craig
authors.initials: C
authors.lastname: Slattery
authors.forename: Michael P
authors.initials: MP
authors.lastname: Ryan
authors.forename: Tara
authors.initials: T
authors.lastname: McMorrow
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019295:Computational Biology / Q000379:methods; D016572:Cyclosporine / Q000009:adverse effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009994:Osmolar Concentration; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; C486715:TXNIP protein, human; D016212:Transforming Growth Factor beta; D016572:Cyclosporine