Cyclosporine A induces senescence in renal tubular epithelial cells.
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.
Jennings
Paul
P
Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria.
Koppelstaetter
Christian
C
Aydin
Sonia
S
Abberger
Thomas
T
Wolf
Anna Maria
AM
Mayer
Gert
G
Pfaller
Walter
W
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
D012333:RNA, Messenger; D016572:Cyclosporine; D004247:DNA