Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease

Sis, B.; Tasanarong, Adis; Khoshjou, Farhad; Dadras, Farahnaz; Solez, Kim; Halloran, Philip F.

doi:10.1038/sj.ki.5002039

Cited by 126 publications

(113 citation statements)

References 25 publications

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“…Telomere shortening is one mechanism of senescence. Several studies reported that telomere length is decreased in patients with emphysema and COPD (32,39), consistent with chronic infection and inflammation, which induce senescence (2,21,24,30,34,35). Considering the cellular stress of recurrent exacerbations of infection and inflammation in CF, we evaluated whether CF lung airway epithelial cells also had telomere shortening.…”

Section: Resultsmentioning

confidence: 99%

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Increased expression of senescence markers in cystic fibrosis airways

Fischer¹,

Wong²,

Degan

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cystic Fibrosis (CF) is a chronic lung disease characterized by chronic neutrophilic airway inflammation and increased levels of neutrophil elastase (NE) in the airways. We have previously reported that NE treatment triggers cell cycle arrest. Cell cycle arrest can lead to senescence, a complete loss of replicative capacity. Importantly, senescent cells can be proinflammatory and would perpetuate CF chronic inflammation. By immunohistochemistry, we evaluated whether airway sections from CF and control subjects expressed markers of senescence, including p16INK4a(p16), a cyclin-dependent kinase inhibitor, phospho-Histone H2A.X (γH2A.X), and phospho-checkpoint 2 kinase (phospho-Chk2), which are also DNA damage response markers. Compared with airway epithelium from control subjects, CF airway epithelium had increased levels of expression of all three senescence markers. We hypothesized that the high load of NE in the CF airway triggers epithelial senescence by upregulating expression of p16, which inhibits cyclin-dependent kinase 4 (CDK4). Normal human bronchial epithelial (NHBE) cells, cultured in air-liquid interface were treated with NE (0, 200, and 500 nM) to induce visible injury. Total cell lysates were collected and evaluated by Western analysis for p16 protein expression and CDK4 kinase activity. NE significantly increased p16 expression and decreased CDK4 kinase activity in NHBE cells. These results support the concept that NE triggers expression of senescence markers in CF airway epithelial cells.

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Section: Resultsmentioning

confidence: 99%

“…Inflammation has been reported to initiate senescence in other organs including pancreas, liver, and kidney (2,21,24,30,34,35). In addition, senescent cells exhibit an inflammatory phenotype and produce inflammatory mediators including cytokines, chemokines, and metalloproteases (11,20,38,46).…”

Section: Ink4amentioning

confidence: 99%

Increased expression of senescence markers in cystic fibrosis airways

Fischer¹,

Wong²,

Degan

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Tsuji et al (2004) has shown, for example, that cigarette smoke induces senescence in alveolar epithelial cells. Sis et al (2007) used senescent-associated p16 increases instead of SA-β-Gal to detect senescent cells in kidneys with glomerular disease (GD). GDs include many conditions, which fall into two major categories: glomerulonephritis describes the inflammation of the membrane tissue in the kidney that serves as a filter, separating wastes and extra fluid from the blood; glomerulosclerosis is the scarring or hardening of the tiny blood vessels within the kidney.…”

Section: Cellular Senescence and Diseasementioning

confidence: 99%

Cellular senescence, ageing and disease

Burton

2008

AGE

118

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Cellular senescence is the irreversible growth arrest of individual mitotic cells, which as a consequence display a radically altered phenotype that is thought to impair tissue function and predispose tissues to disease development and/or progression as they gradually accumulate. However, in the past, research into mechanisms of ageing has commonly been researched and treated separately from disease development. This may partly be due to the lack of understanding concerning mechanisms of ageing and the difficulty in implementing what was known into models of disease development. Only in the last 10 years, with increasing knowledge of the senescent phenotype and the ability to detect senescent cells in human tissues, have biologists been able to investigate the relationship between cellular senescence and disease. This review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/ progression of disease.

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“…[18][19][20][21][22] In experimental models, renal transplantation leads to a transient elevation in p21 CIP1/WAF1 , sustained increases of p16…”

mentioning

confidence: 99%

Cellular Senescence Limits Regenerative Capacity and Allograft Survival

Braun

Schmidt

Raiss

et al. 2012

Journal of the American Society of Nephrology

156

146

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Long-term graft survival after kidney transplantation remains unsatisfactory and unpredictable. Interstitial fibrosis and tubular atrophy are major contributors to late graft loss; features of tubular cell senescence, such as increased p16INK4a expression, associate with these tubulointerstitial changes, but it is unknown whether the relationship is causal. Here, loss of the INK4a locus in mice, which allows escape from p16 INK4a -dependent senescence, significantly reduced interstitial fibrosis and tubular atrophy and associated with improved renal function, conservation of nephron mass, and transplant survival. Compared with wild-type controls, kidneys from INK4a 2/2 mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF 2/2 donors had significantly better survival 21 days after life-supporting kidney transplantation and developed less tubulointerstitial changes. This correlated with higher proliferative rates of tubular cells and significantly fewer senescent cells. Taken together, these data suggest a pathogenic role of renal cellular senescence in the development of interstitial fibrosis and tubular atrophy and kidney graft deterioration by preventing the recovery from injury. Inhibiting premature senescence could have therapeutic benefit in kidney transplantation but has to be balanced against the risks of suspending antitumor defenses.

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Accelerated expression of senescence associated cell cycle inhibitor p16INK4A in kidneys with glomerular disease

Cited by 126 publications

References 25 publications

Increased expression of senescence markers in cystic fibrosis airways

Increased expression of senescence markers in cystic fibrosis airways

Cellular senescence, ageing and disease

Cellular Senescence Limits Regenerative Capacity and Allograft Survival

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