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(American Journal of Pathology. 2003;162:1305-1312.)
© 2003 American Society for Investigative Pathology

Telomere Shortening and Cellular Senescence in a Model of Chronic Renal Allograft Rejection

Simone A. Joosten^*, Vanessa van Ham^*, Claire E. Nolan, Maria C. Borrias^*, Alan G. Jardine, Paul G. Shiels, Cees van Kooten^* and Leendert C. Paul^*

From the Department of Nephrology,^* Leiden University Medical Center, Leiden, The Netherlands; and the Department of Surgery, University of Glasgow, Glasgow, United Kingdom

Cellular senescence has been suggested to play a role in the deterioration of renal graft function and has been linked to telomere shortening. We have investigated markers of cellular senescence in the F344 to LEW rat model of chronic renal transplant rejection. Syngeneic and LEW to F344 transplants were used as controls. Substantial telomere shortening was observed in all transplants, including allogeneic and syngeneic grafts from day 7 post-transplant onwards. Ischemia of native F344 kidneys was already sufficient to induce telomere shortening. It is known that shortened telomeres can activate cell cycle regulators, such as p21 and p16. Accordingly, all cases showed a transient p21 increase, with a maximum at day 7 and a sustained expression of p16. Importantly, senescence-associated ß-galactosidase staining, a cytological marker for senescence, was only observed in tubular epithelial cells of chronically rejecting F344 allografts from day 30 post-transplantation onwards. Long-term surviving LEW allografts or syngeneic F344 grafts were negative for senescence-associated ß-galactosidase. In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated ß-galactosidase staining is only present in chronically rejecting kidney grafts.

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