Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells
Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells
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DOI：
10.1152/ajprenal.00429.2014
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发表时间：
2015-02-15
影响因子：
4.2
通讯作者：
Prieto, Minolfa C.
中科院分区：
文献类型：
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作者：
Cuevas, Catherina A.;Gonzalez, Alexis A.;Prieto, Minolfa C.
血管紧张素 II (ANG II) 对肾和肾小管纤维化的影响已被广泛报道。最近的研究表明集合管细胞可以经历间质转化，表明集合管细胞参与间质纤维化。 Wnt/β-catenin 信号通路在发育、器官发生和组织稳态中发挥重要作用；然而，该途径的失调与纤维化有关。在本研究中，我们研究了 AT(1) 受体激活是否通过小鼠集合管细胞系 M-1 中的 β-连环蛋白途径诱导纤连蛋白和 I 型胶原蛋白的表达。 M-1 细胞中的 ANG II (10(-7) M) 处理增加了 mRNA、纤连蛋白和胶原蛋白 I 的蛋白水平、β-连环蛋白靶基因（细胞周期蛋白 D1 和 c-myc）以及肌成纤维细胞表型。 AT(1) 受体阻滞剂坎地沙坦可防止这些影响。用双羟萘酸吡维铵 (pyr; 10(-9) M) 抑制 β-连环蛋白降解，可防止 ANG II 诱导的纤连蛋白、胶原蛋白 I 和 β-连环蛋白靶基因的表达。 ANG II处理以时间依赖性方式促进β-连环蛋白的积累。由于糖原合成酶激酶 3 beta (GSK-3 beta) 的磷酸化会抑制 β-连环蛋白降解，因此我们进一步评估了 ANG II 和 ANG II 加 Pyr 对 p-ser9-GSK-3 beta 水平的影响。 ANG II 依赖性β-连环蛋白水平上调与 GSK-3 β 磷酸化相关。 Pyr 可以防止这些影响。我们的数据表明，在 M-1 集合管细胞中，β-连环蛋白途径介导纤连蛋白和 I 型胶原蛋白对 AT(1) 受体激活的反应。
The contribution of angiotensin II (ANG II) to renal and tubular fibrosis has been widely reported. Recent studies have shown that collecting duct cells can undergo mesenchymal transition suggesting that collecting duct cells are involved in interstitial fibrosis. The Wnt/beta-catenin signaling pathway plays an essential role in development, organogenesis, and tissue homeostasis; however, the dysregulation of this pathway has been linked to fibrosis. In this study, we investigated whether AT(1) receptor activation induces the expression of fibronectin and collagen I via the beta-catenin pathway in mouse collecting duct cell line M-1. ANG II (10(-7) M) treatment in M-1 cells increased mRNA, protein levels of fibronectin and collagen I, the beta-catenin target genes (cyclin D1 and c-myc), and the myofibroblast phenotype. These effects were prevented by candesartan, an AT(1) receptor blocker. Inhibition of the beta-catenin degradation with pyrvinium pamoate (pyr; 10(-9) M) prevented the ANG II-induced expression of fibronectin, collagen I, and beta-catenin target genes. ANG II treatment promoted the accumulation of beta-catenin protein in a time-dependent manner. Because phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) inhibits beta-catenin degradation, we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3 beta levels. ANG II-dependent upregulation of beta-catenin protein levels was correlated with GSK-3 beta phosphorylation. These effects were prevented by pyr. Our data indicate that in M-1 collecting duct cells, the beta-catenin pathway mediates the stimulation of fibronectin and collagen I in response to AT(1) receptor activation.