title: Cyclosporine A induces senescence in renal tubular epithelial cells.
abstract: The nephrotoxic potential of the widely used immunosuppressive agent cyclosporine A (CsA) is well recognized. However, the mechanism of renal tubular toxicity is not yet fully elucidated. Chronic CsA nephropathy and renal organ aging share some clinical features, such as renal fibrosis and tubular atrophy, raising the possibility that CsA may exert some of its deleterious effects via induction of a stress-induced senescent phenotype. We investigated this hypothesis in HK-2 cells and primary proximal tubular cells in vitro. CsA induced the production of H2O2, caused cell cycle arrest in the G0/G1 phase, and inhibited DNA synthesis. Furthermore, CsA exposure lead to a reduction of telomere length, increased p53 serine 15 phosphorylation, and caused an upregulation of the cell cycle inhibitor p21(Kip1) (CDKN1A) mRNA levels. CsA caused an increase in p16(INK4a) (CDKN2A) expression after a 13-day exposure in primary proximal tubular cells but not in HK-2 cells. Coincubation of cells with CsA and catalase was able to prevent telomere shortening and partially restored DNA synthesis. In summary, CsA induces cellular senescence in human renal tubular epithelial cells, which can be attenuated by scavenging reactive oxygen species.
authors.affiliation: Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Jennings
authors.forename: Christian
authors.initials: C
authors.lastname: Koppelstaetter
authors.forename: Sonia
authors.initials: S
authors.lastname: Aydin
authors.forename: Thomas
authors.initials: T
authors.lastname: Abberger
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Wolf
authors.forename: Gert
authors.initials: G
authors.lastname: Mayer
authors.forename: Walter
authors.initials: W
authors.lastname: Pfaller
mesh_terms: D000375:Aging / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D016572:Cyclosporine / Q000009:adverse effects*; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology*; D009336:Necrosis; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D016572:Cyclosporine; D004247:DNA