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

• 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
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590877/
• 关键词: ポドサイト; FSGS; ノッチシグナル; ノッチ; 壁側上皮細胞; Notchシグナル; 糸球体硬化; γ-secretase

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.

塌陷性局灶节段性肾小球硬化症（cFSGS）是一种进行性肾脏疾病，其特征是肾小球塌陷伴上皮增生。在这里，我们使用具有免疫毒素诱导的足细胞特异性损伤的 cFSGS 转基因小鼠模型来确定 Notch 信号传导在其发病机制中的作用。小鼠表现出足细胞进行性丧失和严重蛋白尿，并伴有 cFSGS 的组织学特征。增生性上皮的足细胞遗传标签呈阴性，但壁上皮细胞标记claudin-1呈阳性，并表达Notch1、Jagged1和Hes1 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记物（α-平滑肌肌动蛋白、波形蛋白和 Snail1）相关。体外Notch抑制抑制了这​​些表型转录本和Notch依赖性细胞迁移。此外，在我们的cFSGS模型中，体内Notch抑制显着减少了壁上皮细胞病变，但使蛋白尿和组织病理学恶化。因此，异常的 Notch1 介导的壁上皮细胞迁移和表型变化似乎是 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，以补偿因进行性足细胞损失而破坏的滤过屏障。

项目成果

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。

• 发表时间: 2012
• 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

• 发表时间: 2011
• 作者: Hida M;Nagata M;Awazu M
• 通讯作者: Awazu M

Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss.

• DOI: 10.1038/ki.2013.48
• 发表时间: 2013-06
• 期刊: Kidney international
• 影响因子: 19.6
• 作者: Ueno T;Kobayashi N;Nakayama M;Takashima Y;Ohse T;Pastan I;Pippin JW;Shankland SJ;Uesugi N;Matsusaka T;Nagata M
• 通讯作者: Nagata M

シンポジウム、腎糸球体のリモデリングと分節性硬化

研讨会，肾小球重塑和节段性硬化症

• 发表时间: 2011
• 作者: 寺井秀樹;副島研造;渡辺真純;猶木克彦;安田浩之;里見良輔;中山荘平;依田聡;池村辰之介;佐藤崇;諸澤麻衣子;浅野浩一郎;Onoe H;長田道夫
• 通讯作者: 長田道夫

Focal segmental glomerulosclerosis as a complication of hepatitis B virus infection

• DOI: 10.1093/ndt/gfq600
• 发表时间: 2011-01-01
• 期刊: NEPHROLOGY DIALYSIS TRANSPLANTATION
• 影响因子: 6.1
• 作者: Sakai, Kentaro;Morito, Naoki;Yamagata, Kunihiro
• 通讯作者: Yamagata, Kunihiro