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, Leendert C. Paul

    Research output: Contribution to journalArticle

    Abstract

    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 beta-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 beta-galactosidase. In conclusion, ischemia during transplantation results in telomere shortening and subsequent activation of p21 and p16, whereas senescence-associated beta-galactosidase staining is only present in chronically rejecting kidney grafts.
    Original languageUndefined/Unknown
    Pages (from-to)1305-1312
    Number of pages8
    JournalAmerican Journal of Pathology
    Volume162
    Issue number4
    DOIs
    Publication statusPublished - Apr 2003

    Keywords

    • telomere shortening
    • cellular senescence
    • chronic renal allograft rejection
    • renal graft function
    • chronic renal transplant rejection

    Cite this

    Joosten, S. A., Ham, V. V., Nolan, C. E., Borrias, M. C., Jardine, A. G., Shiels, P. G., Kooten, C. V., & Paul, L. C. (2003). Telomere shortening and cellular senescence in a model of chronic renal allograft rejection. American Journal of Pathology, 162(4), 1305-1312. https://doi.org/10.1016/S0002-9440(10)63926-0