Feng Ye, Liang Yan, Ren Jiafa, Dai Chunsun
Center for Kidney Disease, Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Kidney Dis (Basel). 2018 Jun;4(2):95-103. doi: 10.1159/000488984. Epub 2018 May 23.
Wnt/β-catenin, an evolutionary conserved signaling pathway, plays an essential role in modulating kidney injury and repair. Our previous studies demonstrated that Wnt/β-catenin signaling could stimulate macrophage M2 polarization and contribute to kidney fibrosis. However, whether canonical Wnt signaling activation leads to macrophage proliferation during kidney fibrosis remains to be determined.
In this study, a mouse model with macrophage-specific β-catenin gene deletion was generated and a unilateral ureter obstruction (UUO) model was created.
In a mouse model with UUO nephropathy, deletion of β-catenin in macrophages attenuated macrophage proliferation and accumulation in kidney tissue. Wnt3a, a well-known canonical Wnt signaling stimulator, could markedly promote macrophage proliferation, whereas blocking canonical Wnt signaling with ICG-001 or ablating β-catenin could largely inhibit macrophage colony-stimulating factor-stimulated macrophage proliferation. Wnt3a treatment could time-dependently upregulate cyclin D1 protein expression and blocking β-catenin signaling could downregulate it.
These results demonstrate that Wnt/ β-catenin signaling is essential for promoting macrophage proliferation during kidney fibrosis.
Wnt/β-连环蛋白是一条进化保守的信号通路，在调节肾损伤和修复中起重要作用。我们之前的研究表明，Wnt/β-连环蛋白信号可刺激巨噬细胞M2极化并促进肾纤维化。然而，在肾纤维化过程中，经典Wnt信号激活是否导致巨噬细胞增殖仍有待确定。
在本研究中，构建了巨噬细胞特异性β-连环蛋白基因缺失的小鼠模型，并建立了单侧输尿管梗阻（UUO）模型。
在UUO肾病小鼠模型中，巨噬细胞中β-连环蛋白的缺失减弱了巨噬细胞在肾组织中的增殖和积聚。Wnt3a是一种著名的经典Wnt信号刺激剂，可显著促进巨噬细胞增殖，而用ICG-001阻断经典Wnt信号或剔除β-连环蛋白可在很大程度上抑制巨噬细胞集落刺激因子刺激的巨噬细胞增殖。Wnt3a处理可时间依赖性地上调细胞周期蛋白D1蛋白表达，而阻断β-连环蛋白信号可下调其表达。
这些结果表明，Wnt/β-连环蛋白信号对于促进肾纤维化过程中巨噬细胞增殖至关重要。
