TRIP13-deficient tubular epithelial cells are susceptible to apoptosis following acute kidney injury.
TRIP13-deficient tubular epithelial cells are susceptible to apoptosis following acute kidney injury.
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DOI：
10.1038/srep43196
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发表时间：
2017-03-03
影响因子：
4.6
通讯作者：
Park F
中科院分区：
文献类型：
--
作者：
Pressly JD;Hama T;Brien SO;Regner KR;Park F
遗传、环境或生物损伤对肾小管上皮细胞的损伤可启动复杂的信号机制，促进肾脏修复和功能恢复。在这项研究中，我们证明了甲状腺受体相互作用蛋白13(TRIP13)是肾缺血再灌注损伤(IRI)后肾小管上皮细胞修复的关键调节剂，IRI是一种常见的肾脏应激源。在单侧肾脏IRI治疗的Trip13Gt/Gthypomph型小鼠中，与对侧肾脏相比，IRI治疗的小鼠肾脏在实验的168 小时内被确定为持续性的肾小管上皮细胞损伤。损伤的上皮细胞与DNA损伤水平(ɣH_2AX)和凋亡标志物(P53、裂解的Caspase-7和TUNEL阳性细胞)有关。相应地，TRIP13被发现直接与P53辅助因子四肽重复结构域5(TTC5)相互作用，并且在过氧化氢存在下，在小鼠内髓集合管细胞中TRIP13的基因敲除显示P53在丝氨酸15的活性增加。总之，这些研究表明，TRIP13不足增加了受损的肾小管上皮细胞走向凋亡细胞的易感性。
Damage to renal tubular epithelial cells by genetic, environmental, or biological insults can initiate complex signaling mechanisms that promote kidney repair and functional recovery. In this study, we demonstrated that thyroid receptor interacting protein 13 (TRIP13) is a critical modulator of tubular epithelial cell repair following ischemia‐reperfusion injury (IRI), a common type of renal stressor. In Trip13Gt/Gthypomorph mice treated with unilateral renal IRI, persistent tubular epithelial cell damage was determined in the IRI-treated kidney throughout the 168 hours of experimental period compared to the contralateral kidneys. The damaged epithelial cells were associated with increased levels of DNA damage (ɣH2AX) and apoptotic markers (p53, cleaved caspase-7, and TUNEL-positive cells). Correspondingly, TRIP13 was found to directly interact with Tetratricopeptide Repeat Domain 5 (TTC5), a p53 co‐factor, and genetic knockdown of TRIP13 in murine inner medullary collecting duct cells in the presence of hydrogen peroxide showed increased activity of p53 at Serine 15. In all, these studies suggest that insufficient TRIP13 increased the susceptibility of damaged tubular epithelial cells to progress towards apoptotic cell death.