Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD
Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD
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经典 Wnt 抑制剂可改善人 ADPKD 小鼠直系同源细胞的囊肿发生
DOI：
10.1172/jci.insight.95874
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发表时间：
2018-03-08
期刊：
影响因子：
8
通讯作者：
Wu，Dianqing
中科院分区：
文献类型：
--
作者：
Li，Ao;Xu，Yuchen;Wu，Dianqing
常染色体显性遗传性多囊肾病(ADPKD)可由PKD1或PKD2基因突变引起。PKD1基因产物是一种Wnt细胞表面受体。我们之前的研究表明，在小鼠胚胎成纤维细胞、肾上皮细胞和分离的肾脏集合管细胞中，PKD2基因产物PC2的缺失会增加β-连环蛋白信号。然而，目前尚不清楚β-连环蛋白信号在多囊肾病表型中是否发挥作用，或者Wnt抑制剂是否可以阻止ADPKD疾病模型中的囊性形成。在这里，利用遗传学和药理学方法，我们证明了由PC2缺乏引起的β-连环蛋白信号的升高对人类ADPKD的同源小鼠的疾病表型有显著的贡献。从药物上抑制β-连环蛋白的稳定性或产生成熟的Wnt蛋白，或从基因上减少β-连环蛋白的表达，可以抑制肾囊肿的形成，改善肾功能，延长多囊肾病小鼠的生存时间。我们的研究清楚地证明了β-连环蛋白信号在与PKD2突变相关的疾病表型中的重要性。它还描述了两种Wnt抑制剂XAV939和LGK974对各种Wnt信号靶点的影响，作为ADPKD的一种潜在治疗方式，目前还没有有效的治疗方法。
Autosomal dominant polycystic kidney disease (ADPKD) can be caused by mutations in the PKD1 or PKD2 genes. The PKD1 gene product is a Wnt cell-surface receptor. We previously showed that a lack of the PKD2 gene product, PC2, increases β-catenin signaling in mouse embryonic fibroblasts, kidney renal epithelia, and isolated renal collecting duct cells. However, it remains unclear whether β-catenin signaling plays a role in polycystic kidney disease phenotypes or if a Wnt inhibitor can halt cyst formation in ADPKD disease models. Here, using genetic and pharmacologic approaches, we demonstrated that the elevated β-catenin signaling caused by PC2 deficiency contributes significantly to disease phenotypes in a mouse ortholog of human ADPKD. Pharmacologically inhibiting β-catenin stability or the production of mature Wnt protein, or genetically reducing the expression of Ctnnb1 (which encodes β-catenin), suppressed the formation of renal cysts, improved renal function, and extended survival in ADPKD mice. Our study clearly demonstrates the importance of β-catenin signaling in disease phenotypes associated with Pkd2 mutation. It also describes the effects of two Wnt inhibitors, XAV939 and LGK974, on various Wnt signaling targets as a potential therapeutic modality for ADPKD, for which there is currently no effective therapy.