TELOMERE EROSION AND ALTERED SENESCENCE ASSOCIATED GENE EXPRESSION IN A RAT TRANSPLANT MODEL OF CHRONIC DYSFUNCTION.

 

CE Nolan1, SA Joosten2, V van Ham2, MC Borias2, C van Kooten2, LC Paul2, AG Jardine3 and PG Shiels1.

 

1 University of Glasgow, Division of Cancer Sciences and Mol Pathol, and 3 Division of Cardiovascular and Medical Sciences, Western Infirmary Glasgow, 44 Church St, Glasgow G11 6NT. 2 Dept Nephrology, C3P, Leiden University Medical Center, Albinusdreff2, Leiden, 2333ZA, Netherlands.

 

The explosion of free radicals following ischaemia and reperfusion (I/R) injury is capable of causing massive intracellular damage to lipids, protein and DNA. This damage may manifest as shortening of telomeres, the protective nucleoprotein complexes that cap the ends of mammalian chromosomes. These G-rich sequences are particularly susceptible to double-stranded DNA damage, and in such a situation, many of the associated protective telomeric proteins are recruited to sites of damage throughout the chromosome, leaving the telomere exposed. Consequently, although less profound damage may result in cellular repair, albeit at the expense of telomere length, overwhelming damage will activate apoptotic mechanisms. This has undoubted implications for transplantation, as transplanted cells demonstrating accelerated senescence at a cellular level will be less able to cope with further immune and non-immune mediated stresses at the organ level, and may therefore predetermine the success of the graft.

 

To investigate this further, telomere length and senescence associated gene expression were analysed in a rat transplant model of chronic allograft dysfunction, namely Fischer 344/Lewis rat model (Joosten et al Am J Pathol 2003;162:1305-12). Telomere length was measured 60 days post transplant using a novel TeloGLOTM technique (Promega USA), and XRCC5 expression, a telomere-associated protein involved in DNA repair and intrinsically coupled to I/R, was measured using real time quantitative PCR (TaqMANTM). Massive telomere loss is demonstrated in allo- and syngeneic transplants, reinforcing the involvement of a non-immune mediated mechanism, and XRCC5 expression is increased in allogeneic transplants. These data indicate that renal allografts are subject to substantial oxidant stress at the time of transplantation, and highlight novel target areas for therapeutic intervention and prognostic evaluation of grafts.

 


 

 


TELOMERE EROSION AND ALTERED SENESCENCE ASSOCIATED GENE EXPRESSION IN A RAT TRANSPLANT MODEL OF CHRONIC DYSFUNCTION.

 

CE Nolan1, SA Joosten2, V van Ham2, MC Borias2, C van Kooten2, LC Paul2, AG Jardine3 and PG Shiels1.

 

Mailing address for contact:

 

Dr PG Shiels

University Dept Surgery

Western Infirmary

44 Church St

Glasgow G11 6NT

Scotland

Tel       0141 211 2762

Fax      0141 211 1972

Email    P.Shiels@clinmed.gla.ac.uk