Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.
Tenascin-C protects against acute kidney injury by recruiting Wnt ligands.
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Tenascin-C 通过招募 Wnt 配体预防急性肾损伤
DOI：
10.1016/j.kint.2018.08.029
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发表时间：
2019-01
影响因子：
19.6
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Chen S;Fu H;Wu S;Zhu W;Liao J;Hong X;Miao J;Luo C;Wang Y;Hou FF;Zhou L;Liu Y
急性肾损伤（阿基）的发展是一个复杂的过程，涉及肾小管、炎症和血管成分，但对间质微环境的作用知之甚少。我们以前已经表明，细胞外基质糖蛋白腱生蛋白-C（TNC）诱导纤维化的肾脏。在缺血再灌注损伤（IRI）或顺铂诱导的阿基小鼠模型中，TNC在损伤部位重新诱导，并定位于肾皮质。心脏手术后阿基患者的TNC蛋白循环水平也升高。在体内通过shRNA敲低TNC可加重缺血性或毒性损伤后的阿基。这种作用与肾β-连环蛋白表达减少相关，表明对Wnt信号传导的影响。在体外，TNC保护肾小管上皮细胞免于凋亡，并增强Wnt 1介导的β-catenin激活。免疫共沉淀显示TNC与Wnt配体物理相互作用。此外，从IRI小鼠制备的富含TNC的肾组织支架能够从离体周围环境中募集和浓缩Wnt配体。在该离体模型中募集Wnt配体的能力在TNC耗尽后降低。这些研究表明，TNC在损伤部位被特异性诱导，并招募Wnt配体，从而为阿基后的肾小管修复和再生创造了有利的微环境。
The development of acute kidney injury (AKI) is a complex process involving tubular, inflammatory, and vascular components, but less is known about the role of the interstitial microenvironment. We have previously shown that the extracellular matrix glycoprotein tenascin-C (TNC) is induced in fibrotic kidneys. In mouse models of AKI induced by ischemia-reperfusion injury (IRI) or cisplatin, TNC was induced de novo in the injured sites and localized to the renal interstitium. The circulating level of TNC protein was also elevated in AKI patients after cardiac surgery. Knockdown of TNC by shRNA in vivo aggravated AKI after ischemic or toxic injury. This effect was associated with reduced renal β-catenin expression, suggesting an impact on Wnt signaling. In vitro, TNC protected tubular epithelial cells against apoptosis and augmented Wnt1-mediated β-catenin activation. Co-immunoprecipitation revealed that TNC physically interacts with Wnt ligands. Furthermore, a TNC-enriched kidney tissue scaffold prepared from IRI mice was able to recruit and concentrate Wnt ligands from the surrounding milieu ex vivo. The ability to recruit Wnt ligands in this ex vivo model diminished after TNC depletion. These studies indicate that TNC is specifically induced at sites of injury and recruits Wnt ligands, thereby creating a favorable microenvironment for tubular repair and regeneration after AKI.
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