Increased hepatic telomerase activity in a rat model of iron overload: a role for altered thiol redox state?
Telomeres are repeated sequences at chromosome ends that are incompletely replicated during mitosis. Telomere shortening caused by proliferation or oxidative damage culminates in replicative arrest and senescence, which may impair regeneration during chronic liver injury. Whereas the effects of experimental liver injury on telomeres have received little attention, prior studies suggest that telomerase, the enzyme complex that catalyzes the addition of telomeric repeats, is protective in some rodent liver injury models. Thus, the aim of this study was to determine the effects of iron overload on telomere length and telomerase activity in rat liver. Mean telomere lengths were similar in iron-loaded and control livers. However, telomerase activity was increased 3-fold by iron loading, with no change in levels of TERT mRNA or protein. Because thiol redox state has been shown to modulate telomerase activity in vitro, hepatic thiols were assessed. Significant increases in GSH (1.5-fold), cysteine (15-fold), and glutamate cysteine ligase activity (1.5-fold) were observed in iron-loaded livers, whereas telomerase activity was inhibited by treatment with N-ethylmaleimide. This is the first demonstration of increased telomerase activity associated with thiol alterations in vivo. Enhanced telomerase activity may be an important factor contributing to the resistance of rodent liver to iron-induced damage.
Brown
Kyle E
KE
Iowa City Veterans Administration Medical Center, Iowa City, IA, USA. kyle-brown@uiowa.edu
Meleah Mathahs
M
M
Broadhurst
Kimberly A
KA
Coleman
Mitchell C
MC
Ridnour
Lisa A
LA
Schmidt
Warren N
WN
Spitz
Douglas R
DR
D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005978:Glutathione / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000633:toxicity; D019190:Iron Overload / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects*
D013438:Sulfhydryl Compounds; D007501:Iron; D019098:Telomerase; D005978:Glutathione; D003545:Cysteine