Cellular Senescence Limits Regenerative Capacity and Allograft Survival
Cellular Senescence Limits Regenerative Capacity and Allograft Survival
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DOI：
10.1681/asn.2011100967
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发表时间：
2012-09-01
影响因子：
13.6
通讯作者：
Melk, Anette
中科院分区：
文献类型：
--
作者：
Braun, Heidi;Schmidt, Bernhard M. W.;Melk, Anette
肾移植后的长期移植物存活率仍然不能令人满意和不可预测。间质纤维化和肾小管萎缩是晚期移植物丢失的主要原因;肾小管细胞衰老的特征，如p16（INK 4a）表达增加，与这些肾小管间质变化相关，但尚不清楚这种关系是否是因果关系。在此，小鼠中INK 4a基因座的丢失，其允许逃避p16（INKa）依赖性衰老，显著减少间质纤维化和肾小管萎缩，并与改善肾功能、保护肾单位质量和移植存活相关。与野生型对照组相比，INK 4a（-/-）小鼠肾脏缺血再灌注损伤后间质纤维化和肾小管萎缩明显减少。一致的是，接受INK 4a/ARF（-/-）供体肾脏移植的小鼠在维持生命的肾脏移植后21天的生存率显着更好，并且肾小管间质变化较少。这与肾小管细胞的较高增殖率和显著较少的衰老细胞相关。总之，这些数据表明肾细胞衰老通过阻止损伤恢复在间质纤维化和肾小管萎缩和肾移植物恶化的发展中起致病作用。抑制过早衰老可能对肾移植有治疗益处，但必须与暂停抗肿瘤防御的风险相平衡。
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 p16(INK4a) 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(INKa)-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(-/-) mice developed significantly less interstitial fibrosis and tubular atrophy after ischemia-reperfusion injury. Consistently, mice that received kidney transplants from INK4a/ARF(-/-) 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.