Gpr48 deficiency induces polycystic kidney lesions and renal fibrosis in mice by activating Wnt signal pathway.
Gpr48 deficiency induces polycystic kidney lesions and renal fibrosis in mice by activating Wnt signal pathway.
复制标题
Gpr48 缺陷通过激活 Wnt 信号通路诱导小鼠多囊肾病变和肾纤维化
DOI：
10.1371/journal.pone.0089835
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ye X
中科院分区：
文献类型：
--
作者：
Dang Y;Liu B;Xu P;Zhu P;Zhai Y;Liu M;Ye X
G蛋白偶联受体48（Gpr 48/Lgr 4）是调节小鼠多个组织发育的重要因子。Gpr 48在肾脏发育中的作用促使我们研究Gpr 48与肾脏疾病的关系。使用Gpr 48敲除小鼠模型，我们观察到66.7%的Gpr 48敲除小鼠在肾脏中出现多囊性病变，而在野生型小鼠的肾脏中没有观察到囊肿。在Gpr 48基因敲除小鼠中，多囊肾病1（PKD 1）和PKD 2的表达也显著降低。细胞外基质蛋白的异常表达可导致Gpr 48基因敲除小鼠多囊肾病的进展和肾纤维化的形成。在Gpr 48基因敲除小鼠中，几种Wnt分子及其受体的表达增加，并且观察到显著的β-连环蛋白核积聚。Wnt/β-catenin信号通路的抑制剂如GSK 3 β和axin 2均丧失功能。Wnt/PCP信号通路也在Gpr 48敲除小鼠中被激活。然而，TGF-β表达和磷酸化Smad 2/3水平没有改变。总的来说，我们的结果表明，Gpr 48基因敲除小鼠患多囊性病变和肾纤维化的风险更大。此外，Gpr 48缺陷导致的多囊性病变和肾纤维化的形成与Wnt信号通路的激活有关，而与TGF-β/Smad信号通路无关。
G protein-coupled receptor 48 (Gpr48/Lgr4) is essential to regulate the development of multiple tissues in mice. The notion that Gpr48 functions in renal development prompted us to investigate the relation between Gpr48 and renal diseases. Using a Gpr48 knockout mice model, we observed that 66.7% Gpr48 null mice developed polycystic lesions in the kidney, while no cysts were observed in the kidneys of wild-type mice. Polycystic kidney disease 1 (PKD1) and PKD2 expressions were also markedly decreased in the Gpr48 knockout mice. Abnormal expressions of exra-cellular matrix protein lead to the progression of polycystic kidney disease and the formation of renal fibrosis in the Gpr48 null mice. The expressions of several Wnt molecules and its receptors were increased and marked β-catenin nuclear accumulation was observed in the Gpr48 null mice. The inhibitors of Wnt/β-catenin signal pathway such as GSK3β and axin2 were loss of function. The Wnt/PCP signaling pathway is also activated in Gpr48 null mice. However, TGF-β expression and phosphorylated Smad2/3 levels were not altered. Collectively, our results showed that Gpr48 null mice are at a greater risk of suffering from polycystic lesions and renal fibrosis. Moreover, the formation of polycystic lesions and renal fibrosis induced by Gpr48 deficiency involves the activation of Wnt signaling pathway but not the TGF-β/Smad pathway.
登录
查看更多内容
影响因子：
--
作者：
Kato, Shigeki;Matsubara, Mitsunobu;Nishimori, Katsuhiko
通讯作者：
Nishimori, Katsuhiko
影响因子：
7.7
作者：
Okada, S;Shikata, K;Makino, H
通讯作者：
Makino, H
影响因子：
13.6
作者：
Benzing, Thomas;Simons, Matias;Walz, Gerd
通讯作者：
Walz, Gerd
DOI：
10.1152/ajprenal.2001.280.3.f540
发表时间：
2001-03-01
影响因子：
4.2
作者：
Obermüller, N;Morente, N;Witzgall, R
通讯作者：
Witzgall, R
影响因子：
7.3
作者：
Hassane, Sabrine;Leonhard, Wouter N.;Peters, Dorien J. M.
通讯作者：
Peters, Dorien J. M.