Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression
Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression
复制标题
Wnt/β-连环蛋白信号传导的持续激活驱动 AKI 发展为 CKD
DOI：
10.1681/asn.2015040449
复制
发表时间：
2016-06-01
影响因子：
13.6
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
--
作者：
Xiao, Liangxiang;Zhou, Dong;Liu, Youhua
AKI越来越被认为是进展为CKD的主要危险因素。然而，控制AKI到CKD进展的因素却知之甚少。在这项研究中，我们使用小鼠的中度(20分钟)和严重(30分钟)缺血/再灌注损伤(IRI)来研究这一问题。中度IRI导致急性肾功能衰竭和一过性Wnt/β-catenin激活，随后肾脏形态和功能恢复。然而，严重的IRI导致Wnt/β-catenin的持续和过度激活，并伴随着以间质肌成纤维细胞活化和细胞外基质过度沉积为特征的肾纤维化病变的发展。为了评估持续的Wnt/β-catenin信号在介导AKI到CKD进展中的作用，我们通过过度表达Wnt配体或药物抑制β-catenin来操纵这一信号转导。在体内，在IRI后5天过表达WNT1诱导了β-连环素的激活，并加速了AKI向CKD的进展。相反，在这一点上，小分子抑制剂ICG-001阻断Wnt/β-catenin阻碍了AKI向CKD的进展。在体外，Wnt配体诱导肾间质成纤维细胞活化，促进纤维连接蛋白的表达。然而，在去除Wnt配体后，激活的成纤维细胞很容易恢复到静止的表型，这表明成纤维细胞的激活需要持续的Wnt信号。这些结果表明，Wnt/β-catenin信号的持续激活，但不是暂时的，在推动AKI向CKD进展方面起着决定性的作用。
AKI is increasingly recognized as a major risk factor for progression to CKD. However, the factors governing AKI to CKD progression are poorly understood. In this study, we investigated this issue using moderate (20 minutes) and severe (30 minutes) ischemia/reperfusion injury (IRI) in mice. Moderate IRI led to acute kidney failure and transient Wnt/beta-catenin activation, which was followed by the restoration of kidney morphology and function. However, severe IRI resulted in sustained and exaggerated Wnt/beta-catenin activation, which was accompanied by development of renal fibrotic lesions characterized by interstitial myofibroblast activation and excessive extracellular matrix deposition. To assess the role of sustained Wnt/beta-catenin signaling in mediating AKI to CKD progression, we manipulated this signaling by overexpression of Wnt ligand or pharmacologic inhibition of beta-catenin. In vivo, overexpression of Wnt1 at 5 days after IRI induced beta-catenin activation and accelerated AKI to CKD progression. Conversely, blockade of Wnt/beta-catenin by small molecule inhibitor ICG-001 at this point hindered AKI to CKD progression. In vitro, Wnt ligands induced renal interstitial fibroblast activation and promoted fibronectin expression. However, activated fibroblasts readily reverted to a quiescent phenotype after Wnt ligands were removed, suggesting that fibroblast activation requires persistent Wnt signaling. These results indicate that sustained, but not transient, activation of Wnt/beta-catenin signaling has a decisive role in driving AKI to CKD progression.