Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease.
The cell cycle inhibitor p16(INK4A) (also known as cyclin-dependent kinase inhibitor 2A) is expressed in vivo in many tissues with age. The exposure of certain chronic stresses can trigger p16(INK4A) expression and a senescence-like phenotype. We studied whether p16(INK4A) expression is induced in glomerular disease (GD). We performed p16(INK4A) immunostaining on 35 biopsies with GD, 12 tubulointerstitial nephritis (TIN), and 19 normal live donor kidneys at transplantation. Based on values for 42 normal kidneys, we calculated expected nuclear p16(INK4A) expression for age and compared the observed values in diseased kidneys to those expected for age. In GD, p16(INK4A) expression was strikingly increased in glomerular and interstitial cell nuclei compared to normals and TIN, and could not be attributed to age (P<0.05). By multivariate analyses, GD was independently associated with increased nuclear p16(INK4a) expression in glomeruli (P<0.001) and interstitium (P=0.01). The p16(INK4A) expression in glomerular and interstitial cell nuclei, and tubular cytoplasm was higher in kidneys with proteinuria and with atrophy/fibrosis (P<0.05). Older age was associated with increased nuclear p16(INK4a) expression in tubules (P=0.01), and interstitial inflammation was associated with increased nuclear p16(INK4a) expression in interstitial cells (P=0.001). The p16(INK4a) staining in tubular cytoplasm was increased in both GD and TIN compared to normals (P<0.001), and was not related to age (P>0.05). Thus, kidneys with GD display increased expression of senescence marker p16(INK4A) in glomerular and interstitial cell nuclei compared to kidneys with normal aging or TIN. The findings suggest a role for somatic cell senescence mechanisms in progression of GD.
Sis
B
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Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
Tasanarong
A
A
Khoshjou
F
F
Dadras
F
F
Solez
K
K
Halloran
P F
PF
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D002453:Cell Cycle; D002467:Cell Nucleus / Q000737:chemistry; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000378:metabolism*; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D005921:Glomerulonephritis / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial / Q000378:metabolism / Q000473:pathology; D011507:Proteinuria / Q000378:metabolism
D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16