Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments
Autophagy Induces Prosenescent Changes in Proximal Tubular S3 Segments
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DOI：
10.1681/asn.2014111059
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发表时间：
2016-06-01
影响因子：
13.6
通讯作者：
Schmitt, Roland
中科院分区：
文献类型：
--
作者：
Baisantry, Arpita;Bhayana, Sagar;Schmitt, Roland
有证据表明，自噬促进细胞衰老的发展。由于细胞衰老有助于肾脏衰老并促进从阿基到CKD的进展，因此我们研究了肾小管自噬对衰老诱导的潜在作用。与对照小鼠的肾脏相比，缺血/再灌注损伤后30天，在近端肾小管S3段（Atg 5（Delta flox/Delta flox））中选择性消融自噬相关5（Atg 5）的小鼠肾脏呈现出显著更少的肾小管衰老，减少的间质纤维化和上级肾功能。为了将这种长期结果与早期损伤过程的差异相关联，在再灌注后2小时和3天对肾脏进行了分析。值得注意的是，与对照小鼠的肾脏相比，Atg 5（Delta flox/Delta flox）肾脏在2小时时在外髓S3段中显示更多的细胞死亡，但在第3天时显示较少的肾小管损伤和炎症。这些数据表明，缺乏自噬阻止了严重受损的肾小管细胞的早期存活机制。然而，如果这种受损细胞持续存在，那么它们可能导致适应不良的修复和促炎变化，从而促进衰老表型和CKD的发展。
Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Delta flox/Delta flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Delta flox/Delta flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD.