Increased expression of p16(INK4a) and p27(Kip1) cyclin-dependent kinase inhibitor genes in aging human kidney and chronic allograft nephropathy

Chkhotua, Archil; Gabusi, Elena; Altimari, Annalisa; d’Errico, Angelo; Yakubovich, Michaela; Vienken, Joerg; Stefoni, Sergio; Chieco, Pasquale; Yussim, A; Grigioni, Francesco

doi:10.1016/s0272-6386(03)00363-9

Cited by 103 publications

(62 citation statements)

References 26 publications

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“…18,21 To test our findings in the transplant setting, we performed transplants from INK4a/ ARF 2/2 as well as wild-type mice, which are both on a C57BL/ 6 background, into fully MHC-mismatched wild-type mice on a C3H background. Importantly, the transplant model allowed us to exclude that a reduced immunologic response was the reason for the better outcome of kidneys from INK4a 2/2 mice after ischemia-reperfusion injury.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…[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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show abstract

“…In contrast, CDK inhibitors inactivate CDK and cause cell-cycle arrest. There is a growing body of literature showing that CDK inhibitors p21 cip1 and p27 kip1 may be critical regulators of GMC hypertrophy (33) and cell senescence (4,34). Zheng et al (5) found that mesangial cells isolated from kidneys of postmenopausal mice were enlarged and had elevated amounts of p27 kip1 protein expression as assessed by immunochemistry.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Connexin 43 Expression by High Glucose Induces Senescence in Glomerular Mesangial Cells

Zhang

Chen

et al. 2006

Journal of the American Society of Nephrology

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Connexin 43 (Cx43) plays an important role in cell differentiation and growth control, but whether it can be regulated by high glucose and whether it can mediate in glomerular mesangial cells (GMC) the phenotype alterations that are induced by high glucose still remain to be explored. In this study, RNA interference and gene transfer techniques were used to knock down and overexpress Cx43 gene in rat GMC to determine the contribution of Cx43 to GMC senescence that was induced by high glucose. The results show that high glucose (30 mM) not only downregulated Cx43 mRNA and protein expression (P < 0.05) but also increased the percentage of senescence-associated ␤-galactosidase (SA-␤-gal) stained cells and expression of p21 cip1 and p27 kip1 (P < 0.05), indicating that high glucose promoted rat GMC senescence. Knocking down Cx43 gene expression significantly increased the percentage of SA-␤-gal stained cells and p27 kip1 and p21 cip1 expression in GMC (P < 0.05), whereas overexpression of Cx43 significantly decreased the percentage of SA-␤-gal stained cells (P < 0.05). These results demonstrate for the first time that downregulation of Cx43 expression by high glucose promotes the senescence of GMC, which may be involved in the pathogenesis of diabetic nephropathy.

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“…92 Overall expression of the senescence marker p16(INK4A) and the percentage of cells expressing p16(INK4A), particularly in the glomerulus, tubules, and interstitial space, are higher in older kidneys than in younger ones. 93,94 Telomere shortening, 42 Dicer-associated microRNAs, 95 and heme oxygenase-regulated autophagy 96 are important new modulators for risk for AKI. Chordin 1-regulated expression of bone morphogenic protein 7 also plays a role in restoring tubular epithelia after AKI.…”

Section: Mechanisms Underlying Akimentioning

confidence: 99%