Treatment of focal segmental glomerulosclerosis by Notch signaling inhibition

通过Notch信号抑制治疗局灶节段性肾小球硬化

基本信息

批准号：
22590877
负责人：
NAGATA Michio
金额：
$ 2.83万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

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.

倒塌的局灶性节段性肾小球硬化（CFSG）是一种进行性肾脏疾病，其特征是肾小球塌陷，上皮增生。在这里，我们使用了具有免疫毒素诱导的足细胞特异性损伤的CFSG的转基因小鼠模型来确定Notch信号在其发病机理中的作用。小鼠暴露了足细胞的进行性逐渐丧失和与CFSG的组织学特征相关的严重蛋白尿。通过转化的培养的私下性上皮细胞中转化的生长因子-β1诱导的增生上皮增强的Notch mRNA表达与间充质标记（α-平滑肌肌动蛋白，波形蛋白和Snail1）相关。 Notch抑制体外抑制了这些表型转录本和依赖Notch的细胞迁移。此外，Notch抑制体内可显着改善顶叶上皮细胞病变，但在我们的CFSGS模型中蛋白尿和组织病理学恶化。这就是异常的Notch1介导的顶叶上皮细胞随表型变化的迁移似乎是CFSG的发病机理的基础。顶叶上皮细胞增生也可能代表适应性反应，以补偿带有渐进性足细胞损失的破坏过滤屏障。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Notch signal induced parietal cells hyperplasia in collapsing FSGS with progressive podocyte loss.

Notch 信号诱导 FSGS 塌陷时壁细胞增生，并伴有进行性足细胞损失。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Fujita H;Hida M;Kanemoto K;Fukuda K;Nagata M;Awazu M;丸茂丈史;120.扇野圭子，副島研造，荒井大輔，石岡宏太，池村辰之介，寺井秀樹，浜本純子，猶木克彦，別役智子;大澤郁朗;Ueno T
通讯作者：
Ueno T

Downregulation of mTOR signaling pathway by maternal nutrient restriction in rat metanephros

母体营养限制对大鼠后肾 mTOR 信号通路的下调