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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/F831    most recent 00005.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Jennings, P. Articles by Pfaller, W. Search for Related Content PubMed PubMed Citation Articles by Jennings, P. Articles by Pfaller, W.

Cyclosporine A induces senescence in renal tubular epithelial cells

¹Division of Physiology, Department of Physiology and Medical Physics, ²Division of Nephrology, and ³Division of Hematology and Oncology, Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria

Submitted 3 January 2007 ; accepted in final form 16 June 2007

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.

p53; p16; p21; telomere; proliferation; cell culture; proximal tubular; reactive oxygen species