Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk
Paracrine Wnt1 Drives Interstitial Fibrosis without Inflammation by Tubulointerstitial Cross-Talk
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DOI：
10.1681/asn.2014121188
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发表时间：
2016-03-01
影响因子：
13.6
通讯作者：
Hunnphreys, Benjamin D.
中科院分区：
文献类型：
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作者：
Maarouf, Omar H.;Aravamudhan, Anusha;Hunnphreys, Benjamin D.
上皮修复不全的AKI是以肾小管间质纤维化为特征的慢性肾脏病的主要致病因素。损伤诱导的上皮细胞分泌前纤维因子被认为是这一联系的基础，但这些因素的特性以及是否需要上皮损伤仍未确定。我们先前发现，在体内，间质周细胞中典型的Wnt信号通路的激活自主地驱动肌成纤维细胞的激活。在这里，我们表明，抑制规范的Wnt信号也在很大程度上阻止了体外转化生长因子β依赖的肌成纤维细胞的激活。为了研究来自近端小管的Wnt配体是否足以导致肾脏纤维化，我们培育了一种新的小鼠品系，该品系具有可诱导的近端小管Wntl分泌。成年小鼠注射赋形剂或三苯氧胺，分别于注射后12周或24周处死。与赋形剂处理的对照组相比，他莫昔芬诱导近端小管WNTL表达的肾脏表现出间质肌成纤维细胞的激活和增殖，并增加了基质蛋白的产生。从这些肾脏分离的PDGF受体β阳性的肌成纤维细胞显示，与对照组相比，规范的Wnt靶基因表达增加。值得注意的是，纤维化的肾脏没有炎性细胞因子表达、白细胞浸润或上皮损伤的证据，尽管每一个都与CKD有密切的组织学联系。这些结果提供了第一个非炎症性肾纤维化的例子。事实上，上皮来源的Wnt配体足以驱动间质纤维化，这一事实为AKI向CKD转变中的不良适应修复假说提供了强有力的支持。
AKI with incomplete epithelial repair is a major contributor to CKD characterized by tubulointerstitial fibrosis. Injury-induced epithelial secretion of profibroticfactors is hypothesized to underlie this link, but the identity of these factors and whether epithelial injury is required remain undefined. We previously showed that activation of the canonical Wnt signaling pathway in interstitial pericytes cell autonomously drives myofibroblast activation in vivo. Here, we show that inhibition of canonical Wnt signaling also substantially prevented TGF beta-dependent myofibroblast activation in vitro. To investigate whether Wnt ligand derived from proximal tubule is sufficient for renal fibrogenesis, we generated a novel mouse strain with inducible proximal tubule Wntl secretion. Adult mice were treated with vehicle or tamoxifen and euthanized at 12 or 24 weeks postinjection. Compared with vehicle-treated controls, kidneys with tamoxifen-induced Wntl expression from proximal tubules displayed interstitial myofibroblast activation and proliferation and increased matrix protein production. PDGF receptor beta-positive myofibroblasts isolated from these kidneys exhibited increased canonical Wnt target gene expression compared with controls. Notably, fibrotic kidneys had no evidence of inflammatory cytokine expression, leukocyte infiltration, or epithelial injury, despite the close histologic correlation of each with CKD. These results provide the first example of noninflammatory renal fibrosis. The fact that epithelial derived Wnt ligand is sufficient to drive interstitial fibrosis provides strong support for the maladaptive repair hypothesis in the AKI to CKD transition.