Tenascin-C promotes acute kidney injury to chronic kidney disease progression by impairing tubular integrity via αvβ6 integrin signaling.
Tenascin-C promotes acute kidney injury to chronic kidney disease progression by impairing tubular integrity via αvβ6 integrin signaling.
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DOI：
10.1016/j.kint.2020.01.026
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发表时间：
2020-05
影响因子：
19.6
通讯作者：
Fu H
中科院分区：
文献类型：
--
作者：
Zhu H;Liao J;Zhou X;Hong X;Song D;Hou FF;Liu Y;Fu H
Tenascin-C是一种细胞外基质糖蛋白，通过协调形成纤维化的小生境在肾脏纤维化中发挥关键作用。在这里，我们证明了Tenascin-C是一种生物标记物，是通过损害肾小管完整性而导致肾纤维化的介体。慢性肾脏疾病(CKD)患者肾活检组织中Tenascin-C水平升高。在225名CKD患者的队列中，与39名健康人相比，尿液中Tenascin-C水平显著升高。此外，CKD患者尿Tenascin-C水平与肾功能不全和纤维化的严重程度相关。在小鼠肾缺血/再灌注性急性肾损伤模型中，Tenascin-C的耗竭保留了肾小管的完整性，减轻了肾纤维化的损害。在体外，Tenascin-C通过诱导部分上皮-间充质转化来损害肾小管细胞的完整性。使用脱细胞的肾组织支架，我们发现富含Tenascin-C的支架在体外促进了肾小管上皮-间充质转化。在机制上，Tenascin-C特异性地诱导肾小管上皮细胞整合素αvβ6，并激活粘着斑激酶。阻断αvβ6整合素或抑制FAK可通过抑制上皮-间充质转化恢复肾小管完整性，减轻肾纤维化。因此，我们的研究强调，Tenascin-C是肾脏纤维化的非侵入性生物标志物和损害肾小管完整性的致病介质。因此，阻断Tenascin-C/αvFAK-6整合素/β信号通路可能成为治疗肾纤维化的新策略。
Tenascin-C is an extracellular matrix glycoprotein that plays a critical role in kidney fibrosis by orchestrating a fibrogenic niche. Here, we demonstrate that tenascin-C is a biomarker and a mediator of kidney fibrogenesis by impairing tubular integrity. Tenascin-C was found to be increased in kidney biopsies from patients with chronic kidney disease (CKD). In a cohort of 225 patients with CKD, the urinary tenascin-C level was markedly elevated, compared to 39 healthy individuals. Moreover, the level of urinary tenascin-C in CKD was correlated with the severity of kidney dysfunction and fibrosis. In mouse model of acute kidney injury-to-CKD induced by ischemia/reperfusion, depletion of tenascin-C preserved tubular integrity and ameliorated renal fibrotic lesions. In vitro, tenascin-C impaired tubular cell integrity by inducing partial epithelial-mesenchymal transition. Using decellularized kidney tissue scaffolds, we found that tenascin-C-enriched scaffolds facilitated tubular epithelial-mesenchymal transition ex vivo. Mechanistically, tenascin-C specifically induced integrins αvβ6 in tubular cells and activated focal adhesion kinase (FAK). Blocking αvβ6 integrins or inhibition of FAK restored tubular integrity by repressing epithelial-mesenchymal transition and alleviated kidney fibrosis. Thus, our studies underscore that tenascin-C is a noninvasive biomarker of kidney fibrogenesis and a pathogenic mediator that impairs tubular integrity. Hence, blockade of the tenascin-C /αvβ6 integrin/FAK signal cascade may be a novel strategy for therapeutic intervention of kidney fibrosis.
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影响因子：
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