Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss.
Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss.
复制标题
DOI：
10.1038/ki.2013.48
复制
发表时间：
2013-06
影响因子：
19.6
通讯作者：
Nagata M
中科院分区：
文献类型：
--
作者：
Ueno T;Kobayashi N;Nakayama M;Takashima Y;Ohse T;Pastan I;Pippin JW;Shankland SJ;Uesugi N;Matsusaka T;Nagata M
塌陷性局灶节段性肾小球硬化症（cFSGS）是一种以肾小球塌陷伴上皮增生为特征的进行性肾脏疾病。在这里，我们使用了一个转基因小鼠模型cFSGS免疫毒素诱导的足细胞特异性损伤，以确定其发病机制中的作用Notch信号。小鼠表现出足细胞的进行性损失和严重的蛋白尿伴随cFSGS的组织学特征。增生上皮的遗传足细胞标签呈阴性，但阳性的壁上皮细胞标志物claudin-1，并表达Notch 1，Jagged 1和Hes 1的mRNA和蛋白。在培养的壁上皮细胞中，转化生长因子-β1诱导的Notch mRNA表达增强与间充质标志物（α-平滑肌肌动蛋白、波形蛋白和Snail 1）相关。Notch抑制在体外抑制这些表型转录和Notch依赖的细胞迁移。此外，在我们的cFSGS模型中，体内Notch抑制显著减少壁上皮细胞病变，但使蛋白尿和组织病理学恶化。因此，异常Notch 1介导的壁上皮细胞迁移与表型变化似乎是cFSGS发病机制的基础。壁上皮细胞增生也可能代表一种适应性反应，以补偿破坏的滤过屏障和进行性足细胞损失。
Collapsing focal segmental glomerulosclerosis (cFSGS) is a progressive kidney disease characterized by glomerular collapse with epithelial hyperplasia. Here we used a transgenic mouse model of cFSGS with immunotoxin-induced podocyte-specific injury to determine the role for Notch signaling in its pathogenesis. The mice exhibited progressive loss of podocytes and severe proteinuria concomitant with histological features of cFSGS. Hyperplastic epithelium was negative for genetic podocyte tags, but positive for the parietal epithelial cell marker claudin-1, and expressed Notch1, Jagged1, and Hes1 mRNA and protein. Enhanced Notch mRNA expression induced by transforming growth factor-β1 in cultured parietal epithelial cells was associated with mesenchymal markers (α-smooth muscle actin, vimentin, and Snail1). Notch inhibition in vitro suppressed these phenotypic transcripts and Notch-dependent cell migration. Moreover, Notch inhibition in vivo significantly decreased parietal epithelial cell lesions but worsened proteinuria and histopathology in our cFSGS model. Thus, aberrant Notch1-mediated parietal epithelial cell migration with phenotypic changes appears to underlie the pathogenesis of cFSGS. Parietal epithelial cell hyperplasia may also represent an adaptive response to compensate for a disrupted filtration barrier with progressive podocyte loss.
登录
查看更多内容
影响因子：
19.6
作者：
SCHWARTZ, MM;LEWIS, EJ
通讯作者：
LEWIS, EJ
影响因子：
6.1
作者：
Shimizu, Maki;Kondo, Shuji;Kagami, Shoji
通讯作者：
Kagami, Shoji
影响因子：
19.6
作者：
Kim, JH;Kim, BK;Lee, HS
通讯作者：
Lee, HS
影响因子：
19.6
作者：
Dijkman, H. B. P. M.;Weening, J. J.;Wetzels, J. F. M.
通讯作者：
Wetzels, J. F. M.
影响因子：
13.2
作者：
Nagata, M;Hattori, M;Watanabe, T
通讯作者：
Watanabe, T