Centre for Human and Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
J Pathol. 2010 Sep;222(1):21-31. doi: 10.1002/path.2734.
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 TGFbeta-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 TGFbeta 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 TGFbeta 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 TGFbeta signalling at the initiation of cystogenesis, but indicate an important role during cyst progression and in fibrogenesis of progressive ADPKD.
常染色体显性多囊肾病 (ADPKD) 是一种常见的遗传性肾脏疾病，其特征是肾脏中有许多充满液体的囊肿和间质纤维化，导致慢性肾衰竭。在囊肿发生过程中，肾小管经历广泛的结构改变，伴随着细胞信号的改变，这些改变直接和/或间接受到 PKD1 和 PKD2 蛋白的调节。由于转化生长因子 (TGF)-β信号调节各种细胞类型的细胞增殖、分化、凋亡、黏附和迁移，我们研究了该信号通路在不同疾病阶段 Pkd1 突变小鼠模型中的激活情况。因此，我们分析了不同 Pkd1 突变小鼠模型在多囊疾病不同阶段 TGFbeta-Smad 信号通路及其靶基因的表达。在起始阶段，囊肿衬里上皮细胞中未观察到 P-Smad2 的核积累，但在 PKD 的轻度和更晚期阶段观察到。这与轻度纤维化和 TGFbeta 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 水平增加一致。在这个阶段，在囊肿周围发现了许多间质成纤维细胞，它们也显示出 P-Smad2 的核定位。然而，骨形态发生蛋白 (BMP) 信号通路不会受到影响，因为与野生型对照相比，P-Smad1/5/8 的核表达和 BMP 靶基因抑制物 DNA 结合/差异-1 (ID-1) 的表达没有改变。此外，进行性 ADPKD 的人肾脏显示出 P-Smad2 的核定位增加，而总的 P-Smad1/5/8 表达较弱。这些结果排除了 TGFbeta 信号在囊肿发生的起始阶段，但表明其在囊肿进展和进行性 ADPKD 的纤维化过程中具有重要作用。
