Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease
Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease
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DOI：
10.1038/sj.ki.5002039
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发表时间：
2007-02-01
影响因子：
19.6
通讯作者：
Halloran, P. F.
中科院分区：
文献类型：
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作者：
Sis, B.;Tasanarong, A.;Halloran, P. F.
细胞周期抑制因子p16(INK4A)(又称细胞周期蛋白依赖性激酶抑制因子2A)在体内随年龄增长而在许多组织中表达。暴露在特定的慢性压力下可以触发p16(Ink4a)的表达和衰老样表型。我们研究了p16(Ink4a)在肾小球疾病(GD)中是否被诱导表达。我们对35例GD患者、12例肾小管间质肾炎(TIN)患者和19例正常活体供肾进行了p16(Ink4a)免疫组织化学染色。基于42个正常肾脏的值，我们计算了预期的核p16(INK4A)随年龄的表达，并将疾病肾脏的观察值与预期的年龄值进行了比较。GD组肾小球和间质细胞核中p16(Ink4a)的表达明显高于正常对照组和TIN组，且与年龄无关(P<；0.05)。经多因素分析，肾小球(P<；0.001)和间质(P=0.01)中p16(INK4a)核表达增加与GD独立相关。P16(Ink4a)在肾小球和间质细胞核及肾小管上皮细胞胞浆中的表达在蛋白尿组和萎缩/纤维化组较高(P<；0.05)。肾间质炎症与间质细胞p16(INK4a)表达增加相关(P=0.001)。GD和TIN患者肾小管上皮细胞胞浆p16(INK4a)表达均高于正常对照组(P<；0.001)，且与年龄无关(P>；0.05)。因此，与正常衰老或TIN相比，GD肾脏肾小球和间质细胞核中衰老标记物p16(INK4A)的表达增加。这一发现表明，体细胞衰老机制在GD的进展中起到了作用。
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.