Increased expression of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy.
BACKGROUND
The goal of the current study was to examine the potential value of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor (CDKI) genes in the process of human kidney aging in vivo, and in the development of chronic allograft nephropathy (CAN).


METHODS
Expression of p16(INK4a) and p27(Kip1) CDKI genes was evaluated and compared in 20 normal human kidney tissues of different ages (range, 21 to 80 years) and in 9 chronically rejected kidney grafts. Age dependency of marker expression was analyzed by the Pearson correlation and linear regression.


RESULTS
Expression of p16 in cortical tubular (CTS) and interstitial (CIS) cells of normal kidney was age dependent (correlation coefficients: 0.608 and 0.726, 95% confidence interval [CI]: 0.227 to 0.828 and 0.417 to 0.884, respectively). Cortical tubular expression of p27 was also correlated with increasing age (0.672, 95% CI: 0.327 to 0.859). Linear regression analyses confirmed the linearity of marker relationship with age (coefficient of determination R(2):0.370, 0.452, and 0.527 for CIS p16, CTS p27, and CTS p16, respectively). The mean chronological and predicted graft ages (53 +/- 21 and 76 +/- 8.9 years, respectively) were significantly different (P = 0.0126). The glomeruli, tubules, and interstitial cells of rejected grafts expressed significantly higher levels of p16 and p27 than normal kidneys. Expression of p16 in glomerular and cortical interstitial cells was higher in grade 3 of CAN than in grade 2 (P = 0.013 and 0.004, respectively).


CONCLUSIONS
The results of the current study show that expression of p16(INK4a) and p27(Kip1) CDKI genes is increased in cortical cells of the aging human kidney and in chronic allograft rejection, supporting the senescence theory of CAN.
Chkhotua
Archil B
AB
National Centre of Urology and Nephrology, Tbilisi, Georgia. achkhotua@hotmail.com
Gabusi
Elena
E
Altimari
Annalisa
A
D'Errico
Antonia
A
Yakubovich
Michaela
M
Vienken
Joerg
J
Stefoni
Sergio
S
Chieco
Pasquale
P
Yussim
Alexander
A
Grigioni
Walter F
WF
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002908:Chronic Disease; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D005786:Gene Expression Regulation; D019942:Genes, p16; D005921:Glomerulonephritis / Q000601:surgery; D006084:Graft Rejection / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007672:Kidney Cortex / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009400:Nephrosclerosis / Q000601:surgery; D014184:Transplantation, Homologous; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27