Stress-induced premature senescence in mononuclear cells from patients on long-term hemodialysis.
BACKGROUND
Repeatedly stimulated mononuclear cells may become senescent prematurely as a result of frequent activation-induced replication. In hemodialysis patients, mononuclear cells are activated repeatedly with each hemodialysis procedure. Characteristics of senescent mononuclear cells include telomere length shortening, increased p53 expression, CD14dim/CD16bright expression, and interleukin overproduction.


METHODS
Peripheral mononuclear cells from 15 hemodialysis patients and 15 age-matched controls were evaluated. Telomere length was assessed by means of fluorescence in situ hybridization in flow cytometry. Expression of p53, CD14/CD16, and intracellular cytokine production (interleukin-1beta [IL-1beta], IL-6, and IL-4) was evaluated by means of flow cytometry using specific antibodies.


RESULTS
Features of senescence were found in a subpopulation of mononuclear cells: (1) accelerated telomere shortening, (2) increased p53 expression, (3) CD14dim/CD16bright expression, and (4) cytokine overproduction (IL-1beta, IL-6, and IL-4). Telomere length shortening was present in 40% +/- 6% of cells from hemodialysis patients compared with less than 5% from age-matched controls. Percentage of cells with short telomeres correlated positively with serum C-reactive protein level, which reflects inflammation. p53 expression was increased in mononuclear cells from hemodialysis patients. Mononuclear cells from hemodialysis patients with decreased telomere length mainly showed the CD14dim/CD16bright phenotype; conversely, cells with normal telomeres presented the CD14bright/CD16dim phenotype. Finally, mononuclear cells from hemodialysis patients, but not controls, spontaneously produced the proinflammatory cytokines IL-1beta and IL-6.


CONCLUSIONS
This study shows the presence of a prematurely senescent subpopulation of peripheral mononuclear cells in hemodialysis patients. These senescent cells probably result from repeated activation and may have a pathophysiological role in the chronic inflammation described in hemodialysis patients.
Ramírez
Rafael
R
Unidad de Investigación, Servicio de Nefrología, Hospital Universitario Reina Sofía, Córdoba, Spain. manuelr.ramirez.sspa@juntadeandalucia.es <manuelr.ramirez.sspa@juntadeandalucia.es>
Carracedo
Julia
J
Soriano
Sagrario
S
Jiménez
Rosario
R
Martín-Malo
Alejandro
A
Rodríguez
Mariano
M
Blasco
Maria
M
Aljama
Pedro
P
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis / Q000009:adverse effects* / Q000379:methods; D013312:Stress, Physiological / Q000150:complications* / Q000235:genetics; D016615:Telomere / Q000235:genetics; D013995:Time
D008070:Lipopolysaccharides