The impact of autophagy on the development of senescence in primary tubular epithelial cells
The impact of autophagy on the development of senescence in primary tubular epithelial cells
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DOI：
10.1080/15384101.2016.1234547
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发表时间：
2016-01-01
期刊：
影响因子：
4.3
通讯作者：
Schmitt, Roland
中科院分区：
文献类型：
--
作者：
Baisantry, Arpita;Bhayana, Sagar;Schmitt, Roland
自噬和衰老是两种不同的途径，在急性肾损伤和肾修复中起重要作用。最近的数据表明，这两个过程可能是相互关联的。为了研究自噬与肾脏衰老之间的潜在联系，我们从野生型小鼠中分离出原代肾小管上皮细胞（PTEC），并监测自噬激活和抑制期间细胞衰老的发生。我们发现，细胞分离和转移到文化的过程与一个强大的基础自噬激活PTEC。通过沉默自噬相关5（Atg 5）特异性抑制自噬抵消了基线条件下衰老标志的发生。减少衰老的功能也观察到Atg 5沉默的PTEC照射后，在H-Ras诱导的致癌衰老，但在这些应力模型的响应是不太均匀的。PTEC中成熟上皮表型的较好保存证实了衰老抑制。有趣的是，用雷帕霉素治疗，其作为自噬的激活剂，也抵消了PTEC中衰老特征的发生。虽然我们将雷帕霉素的抗衰老作用解释为mTOR抑制的自噬独立作用，但Atg 5沉默的更具体方法表明过度活化的自噬可在PTEC中具有促衰老作用。这些结果突出了细胞培养依赖性应激机制、自噬和衰老之间的复杂相互作用。
Autophagy and senescence are 2 distinct pathways that are importantly involved in acute kidney injury and renal repair. Recent data indicate that the 2 processes might be interrelated. To investigate the potential link between autophagy and senescence in the kidney we isolated primary tubular epithelial cells (PTEC) from wild-type mice and monitored the occurrence of cellular senescence during autophagy activation and inhibition. We found that the process of cell isolation and transfer into culture was associated with a strong basal autophagic activation in PTEC. Specific inhibition of autophagy by silencing autophagy-related 5 (Atg5) counteracted the occurrence of senescence hallmarks under baseline conditions. Reduced senescent features were also observed in Atg5 silenced PTEC after -irradiation and during H-Ras induced oncogenic senescence, but the response was less uniform in these stress models. Senescence inhibition was paralleled by better preservation of a mature epithelial phenotype in PTEC. Interestingly, treatment with rapamycin, which acts as an activator of autophagy, also counteracted the occurrence of senescence features in PTEC. While we interpret the anti-senescent effect of rapamycin as an autophagy-independent effect of mTOR-inhibition, the more specific approach of Atg5 silencing indicates that overactivated autophagy can have pro-senescent effects in PTEC. These results highlight the complex interaction between cell culture dependent stress mechanisms, autophagy and senescence.