Cell senescence in rat kidneys in vivo increases with growth and age despite lack of telomere shortening.
BACKGROUND
Somatic cells in vitro have a finite life expectancy before entering a state of senescence, but it is unclear whether this state occurs in vivo in kidney development, growth, and aging. We previously showed that human kidney cortex displays telomere shortening with age. In this study, we compared the structural and functional changes in rat kidney with age to phenomena associated with cellular senescence in vitro.


METHODS
We assessed the changes in Fischer 344 rat kidneys from age 1 to 9 months to define growth and development and from age 9 to 24 months to define aging.


RESULTS
Rat kidney telomeres were approximately 35 to 40 kb long and did not shorten significantly. Expression of mRNA for p16INK4a, a characteristic senescence gene in vitro, was undetectable in most young rats but rose 27 fold during growth and a further 72-fold during aging. p16INK4a protein was localized to the nucleus and increased with age. p16INK4a mRNA also increased in other tissues. Lipofuscin and senescence-associated beta-galactosidase increased in epithelium with growth and aging and their occurrence was significantly associated with each other. Lipofuscin was particularly found in atrophic nephrons.


CONCLUSIONS
We conclude that cell senescence occurs in both growth and aging in rat kidney and may contribute to the age-related pathology. These changes are not due to telomere shortening, but may reflect cumulative environmental stress.
Melk
Anette
A
Department of Medicine, Division of Nephrology and Immunology, University of Alberta, Edmonton, Alberta, Canada. anettemelk@yahoo.com
Kittikowit
Wipawee
W
Sandhu
Irwindeep
I
Halloran
Kieran M
KM
Grimm
Paul
P
Schmidt
Bernhard M W
BM
Halloran
Philip F
PF
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D015870:Gene Expression; D006321:Heart / Q000502:physiology; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000166:cytology* / Q000254:growth & development / Q000502:physiology*; D008062:Lipofuscin; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D013154:Spleen / Q000502:physiology; D016615:Telomere / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D008062:Lipofuscin; D010446:Peptide Fragments; D012333:RNA, Messenger; D001616:beta-Galactosidase