Elevated TGFβ-Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease
Elevated TGFβ-Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease
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DOI：
10.1002/path.2734
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发表时间：
2010-09-01
影响因子：
7.3
通讯作者：
Peters, Dorien J. M.
中科院分区：
文献类型：
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作者：
Hassane, Sabrine;Leonhard, Wouter N.;Peters, Dorien J. M.
常染色体显性遗传性多囊肾病（ADPKD）是一种常见的遗传性肾脏疾病，其特征是肾脏中存在许多充满液体的囊肿和间质纤维化，导致慢性肾功能衰竭。在囊肿形成期间，肾小管经历广泛的结构改变，伴随着改变的细胞信号传导，直接和/或间接受PKD 1和PKD 2蛋白调节。由于转化生长因子（TGF）-β信号调节细胞增殖，分化，凋亡，粘附和迁移的各种类型的细胞，我们研究了这种信号通路在Pkd 1突变小鼠模型在疾病的不同阶段的激活。因此，我们分析了TGF β-Smad信号通路及其靶基因在多囊病不同阶段的不同Pkd 1突变小鼠模型中的表达。P-Smad 2在囊肿衬里上皮细胞中的核积累在起始阶段没有观察到，但在PKD的轻度和更晚期阶段观察到。这与轻度纤维化和TGF β靶基因（如纤连蛋白、I型胶原、纤溶酶原激活物抑制剂1和基质金属蛋白酶-2）的mRNA水平增加相一致。在这个阶段，许多间质成纤维细胞被发现在囊肿周围，这也表明P-Smad 2的核定位。然而，可以拮抗TGF β信号传导的骨形态发生蛋白（BMP）信号传导不受影响，因为与野生型对照相比，P-Smad 1/5/8的核表达和BMP靶基因（DNA结合/差异蛋白-1（ID-1）抑制剂）的表达没有改变。此外，患有进行性ADPKD的人肾脏显示P-Smad 2的核定位增加，而P-Smad 1/5/8的一般表达较弱。这些结果排除了TGF β信号在囊肿形成开始时的作用，但表明在囊肿进展和进行性ADPKD的纤维化中起重要作用。版权所有（C）2010大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited renal disease characterized by many fluid-filled cysts and interstitial fibrosis in the kidneys, leading to chronic renal failure. During cystogenesis the renal tubules undergo extensive structural alterations that are accompanied by altered cellular signalling, directly and/or indirectly regulated by the PKD1 and PKD2 proteins. Since transforming growth factor (TGF)-beta signalling modulates cell proliferation, differentiation, apoptosis, adhesion and migration of various cell types, we studied the activation of this signalling pathway in Pkd1-mutant mouse models at different stages of the disease. Therefore, we analysed expression of the TGF beta-Smad signalling pathway and its target genes in different Pkd1 mutant mouse models in various stages of polycystic disease. Nuclear accumulation of P-Smad2 in cyst lining epithelial cells was not observed in the initiation phase but was observed at mild and more advanced stages of PKD. This coincides with mild fibrosis and increased mRNA levels of TGF beta target genes, such as fibronectin, collagen type I, plasminogen activator inhibitor 1 and matrix metalloproteinase-2. At this stage many interstitial fibroblasts were found around cysts, which also showed nuclear localization for P-Smad2. However, bone morphogenetic protein (BMP) signalling, which can antagonize TGF beta signalling, is not affected, since nuclear expression of P-Smad1/5/8 and expression of the BMP target gene, inhibitor of DNA binding/differential-1 (ID-1) is not altered compared to wild-type controls. Also, human kidneys with progressive ADPKD showed increased nuclear localization of P-Smad2, while in general expression of P-Smad1/5/8 was weak. These results exclude TGF beta signalling at the initiation of cystogenesis, but indicate an important role during cyst progression and in fibrogenesis of progressive ADPKD. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.