Tubular cell dedifferentiation and peritubular inflammation are coupled by the transcription regulator Id1 in renal fibrogenesis.
Tubular cell dedifferentiation and peritubular inflammation are coupled by the transcription regulator Id1 in renal fibrogenesis.
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DOI：
10.1038/ki.2011.469
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发表时间：
2012-05
影响因子：
19.6
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
--
作者：
Li, Yingjian;Wen, Xiaoyan;Liu, Youhua
在肾纤维化过程中，小管上皮-间质转化与小管周围炎症密切相关；然而，目前尚不清楚这两个过程是否有联系。我们之前发现了分化-1抑制剂（Id1），一种基本螺旋-环-螺旋转录因子的显性负拮抗剂，是损伤后小管细胞去分化的主要触发因素。损伤后，Id1在变性的近端小管和集管上皮中选择性诱导，同时存在于细胞质和细胞核中，表明在这两个区室之间穿梭。有趣的是，Id1的上调与小鼠和人类肾病的小管周围炎症有关。在体外，Id1增强了肾上皮细胞的NF-κB信号传导和RANTES表达，从而增强了炎症细胞的募集。Id1也诱导Snail1表达并触发小管上皮去分化。在体内，小鼠体内Id1的基因消融减少了输尿管梗阻后的小管周围炎症和RANTES的小管表达。缺乏Id1的小鼠也受到肌成纤维细胞活化和基质表达的保护，导致阻塞性肾病中总胶原沉积减少。因此，这些结果表明，Id1穿梭于细胞核和细胞质之间，促进小管周围炎症和小管上皮去分化，表明这两个事件在肾纤维化过程中是内在耦合的。
During renal fibrogenesis, tubular epithelial-mesenchymal transition is closely associated with peritubular inflammation; however, it is not clear whether these two processes are connected. We previously identified the inhibitor of differentiation-1 (Id1), a dominant negative antagonist of basic helix-loop-helix transcription factors, as a major trigger of tubular cell dedifferentiation after injury. Id1 was induced selectively in degenerated proximal tubule and collecting duct epithelia after injury and was present in both the cytoplasm and nucleus, suggesting shuttling between these two compartments. Interestingly, the upregulation of Id1 was associated with peritubular inflammation in mouse and human nephropathies. In vitro, Id1 potentiated NF-κB signaling and augmented RANTES expression in kidney epithelial cells, which led to an enhanced recruitment of inflammatory cells. Id1 also induced Snail1 expression and triggered tubular epithelial dedifferentiation. In vivo, genetic ablation of Id1 in mice reduced peritubular inflammation and decreased tubular expression of RANTES following ureteral obstruction. Mice lacking Id1 were also protected against myofibroblast activation and matrix expression, leading to a reduced total collagen deposition in obstructive nephropathy. Thus, these results indicate that Id1 shuttles between nucleus and cytoplasm and promotes peritubular inflammation and tubular epithelial dedifferentiation, suggesting that these two events are intrinsically coupled during renal fibrogenesis.
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发表时间：
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影响因子：
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