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Am J Physiol Renal Physiol (June 27, 2007). doi:10.1152/ajprenal.00005.2007
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Submitted on January 3, 2007
Accepted on June 16, 2007

Cyclosporine A induces senescence in renal tubular epithelial cells

Paul Jennings1, Christian Koppelstaetter2*, Sonia Aydin1, Thomas Abberger1, Anna-Maria Wolf3, Gert Mayer2, and Walter Pfaller1

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

* To whom correspondence should be addressed. E-mail: christian.koppelstaetter{at}uki.at.

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 up-regulation of the cell cycle inhibitor p21Kip1 (CDKN1A ) mRNA levels. CsA caused an increase in p16INK4a (CDKN2A) expression after a 13 day exposure in primary proximal tubular cells but not in HK-2 cells. Co-incubation 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.




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