Aberrant Activation of Notch1 Signaling in Glomerular Endothelium Induces Albuminuria
Aberrant Activation of Notch1 Signaling in Glomerular Endothelium Induces Albuminuria
复制标题
肾小球内皮细胞中 Notch1 信号传导的异常激活诱导蛋白尿
DOI：
10.1161/circresaha.120.316970
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发表时间：
2021-03-05
影响因子：
20.1
通讯作者：
Liu, Ju
中科院分区：
文献类型：
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作者：
Li, Liqun;Liu, Qiang;Liu, Ju
原理：肾小球毛细血管内衬高度特化的有孔内皮，并有助于肾小球滤过屏障。Notch信号通路参与了肾小球滤过屏障的调节，但其在肾小球内皮中的作用尚未被研究，这是由于内皮中Notch通路组分的基因修饰的动物模型的胚胎致死性。目的：确定肾小球内皮中Notch信号通路异常激活的影响及其潜在的分子机制。我们建立了ZEG-NICD 1（notch1胞内结构域）/Tie2-tTA/Tet-O-Cre转基因小鼠模型组成型激活成年小鼠内皮细胞中的Notch1信号传导。三重转基因小鼠出现严重的蛋白尿，肾小球内皮细胞中VE-钙粘蛋白（血管内皮钙粘蛋白）表达显著降低。体外研究表明，NICD 1（Notch 1胞内结构域）慢病毒感染或Notch配体DLL4（δ样配体4）治疗显着降低VE-钙粘蛋白表达和增加单层通透性的人肾小球内皮细胞。此外，Notch1激活或VE-钙粘蛋白基因敲低减少了肾小球内皮糖萼。进一步的研究表明，激活的Notch1抑制VE-钙粘蛋白是通过转录因子SNAI1（snail家族转录抑制因子1）和ERG（Ets相关基因），其结合-373 E-box和-134/-118 ETS（E26转化特异性）元件。我们的研究结果揭示了新的调节机制，即内皮Notch1信号通过转录因子SNAI1和ERG决定VE-钙粘蛋白的水平，导致肾小球滤过屏障功能障碍和诱导蛋白尿。
Rationale:Glomerular capillaries are lined with a highly specialized fenestrated endothelium and contribute to the glomerular filtration barrier. The Notch signaling pathway is involved in regulation of glomerular filtration barrier, but its role in glomerular endothelium has not been investigated due to the embryonic lethality of animal models with genetic modification of Notch pathway components in the endothelium.Objective:To determine the effects of aberrant activation of the Notch signaling in glomerular endothelium and the underlying molecular mechanisms.Methods and Results:We established the ZEG-NICD1 (notch1 intracellular domain)/Tie2-tTA/Tet-O-Cre transgenic mouse model to constitutively activate Notch1 signaling in endothelial cells of adult mice. The triple transgenic mice developed severe albuminuria with significantly decreased VE-cadherin (vascular endothelial cadherin) expression in the glomerular endothelium. In vitro studies showed that either NICD1 (Notch1 intracellular domain) lentiviral infection or treatment with Notch ligand DLL4 (delta-like ligand 4) markedly reduced VE-cadherin expression and increased monolayer permeability of human renal glomerular endothelial cells. In addition, Notch1 activation or gene knockdown of VE-cadherin reduced the glomerular endothelial glycocalyx. Further investigation demonstrated that activated Notch1 suppression of VE-cadherin was through the transcription factors SNAI1 (snail family transcriptional repressor 1) and ERG (Ets related gene), which bind to the -373 E-box and the -134/-118 ETS (E26 transformation-specific) element of the VE-cadherin promoter, respectively.Conclusions:Our results reveal novel regulatory mechanisms whereby endothelial Notch1 signaling dictates the level of VE-cadherin through the transcription factors SNAI1 and ERG, leading to dysfunction of glomerular filtration barrier and induction of albuminuria.