Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney

被引:249
作者
Melk, A [1 ]
Schmidt, BMW
Takeuchi, O
Sawitzki, B
Rayner, DC
Halloran, PF
机构
[1] Univ Alberta, Heritage Med Res Ctr 250, Div Nephrol & Immunol, Dept Med, Edmonton, AB T6G 2S2, Canada
[2] Univ Erlangen Nurnberg, Dept Med Nephrol 4, D-8520 Erlangen, Germany
[3] Nagoya City Univ, Grad Sch Med Sci, Dept Internal Med & Pathophysiol, Nagoya, Aichi, Japan
[4] Dept Med Immunol, Berlin, Germany
基金
加拿大健康研究院;
关键词
kidney; aging; senescence; p16(INK4a); glomerulosclerosis; interstitial fibrosis; tubular atrophy;
D O I
10.1111/j.1523-1755.2004.00438.x
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
Background. Somatic cells in vitro have a finite life expectancy before entering a state of senescence. If this state has an in vivo counterpart, it could contribute to organ aging. We have previously shown that human kidney cortex displays telomere shortening with age. In the present study, we evaluated the relationship between renal age in humans and a number of phenomena associated with cellular senescence in vitro. Methods. Human kidney specimens were obtained at 8 weeks to 88 years of age and were assessed for changes related to aging. Results. We found that human kidneys expressed relatively constant levels of mRNAs for genes potentially related to senescence. Among the candidate genes surveyed, the cell cycle regulator p16(INK4a) emerged with the strongest association with renal aging for both mRNA and protein expression. Proliferation as measured by Ki-67 expression was inversely correlated with p16(INK4a) expression, compatible with a role for p16(INK4a) as an irreversible cell cycle inhibitor. Cyclooxygenase 1 and 2 (COX-1 and COX-2) mRNA expression was elevated in older kidneys, associated with increased protein expression. Comparison of gene expression with age-related histologic changes revealed that glomerulosclerosis correlated with p16(INK4a) and p53, whereas interstitial fibrosis and tubular atrophy were associated with p16(INK4a), p53, COX-1, transforming growth factor-beta1 (TGF-beta1), and heat shock protein A5 (HSPA5). Conclusion. We conclude that some changes observed in cellular senescence in vitro do occur in human kidney with age, particularly in the renal cortex, in some cases correlating with histologic features. P16(INK4a) emerged with the most consistent correlations with age and histologic changes and inversely correlated with cell replication.
引用
收藏
页码:510 / 520
页数:11
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共 50 条
  • [1] Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a
    Alani, RM
    Young, AZ
    Shifflett, CB
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (14) : 7812 - 7816
  • [2] Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts
    Alcorta, DA
    Xiong, Y
    Phelps, D
    Hannon, G
    Beach, D
    Barrett, JC
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1996, 93 (24) : 13742 - 13747
  • [3] Extension of life-span by introduction of telomerase into normal human cells
    Bodnar, AG
    Ouellette, M
    Frolkis, M
    Holt, SE
    Chiu, CP
    Morin, GB
    Harley, CB
    Shay, JW
    Lichtsteiner, S
    Wright, WE
    [J]. SCIENCE, 1998, 279 (5349) : 349 - 352
  • [4] Modulation of Lon protease activity and aconitase turnover during aging and oxidative stress
    Bota, DA
    Van Remmen, H
    Davies, KJA
    [J]. FEBS LETTERS, 2002, 532 (1-2) : 103 - 106
  • [5] CHANG CD, 1991, J BIOL CHEM, V266, P8663
  • [6] ISOLATION OF BIOLOGICALLY-ACTIVE RIBONUCLEIC-ACID FROM SOURCES ENRICHED IN RIBONUCLEASE
    CHIRGWIN, JM
    PRZYBYLA, AE
    MACDONALD, RJ
    RUTTER, WJ
    [J]. BIOCHEMISTRY, 1979, 18 (24) : 5294 - 5299
  • [7] Aberrant cytoplasmic expression of the p16 protein in breast cancer is associated with accelerated tumour proliferation
    Emig, R
    Magener, A
    Ehemann, V
    Meyer, A
    Stilgenbauer, F
    Volkmann, M
    Wallwiener, D
    Sinn, HP
    [J]. BRITISH JOURNAL OF CANCER, 1998, 78 (12) : 1661 - 1668
  • [8] The p16INK4a tumour suppressor protein inhibits αvβ3 integrin-mediated cell spreading on vitronectin by blocking PKC-dependent localization of αvβ3 to focal contacts
    Fåhraeus, R
    Lane, DP
    [J]. EMBO JOURNAL, 1999, 18 (08) : 2106 - 2118
  • [9] GERADTS J, 1995, CANCER RES, V55, P6006
  • [10] TELOMERES SHORTEN DURING AGING OF HUMAN FIBROBLASTS
    HARLEY, CB
    FUTCHER, AB
    GREIDER, CW
    [J]. NATURE, 1990, 345 (6274) : 458 - 460