Aberrant Activation of Notch1 Signaling in Glomerular Endothelium Induces Albuminuria

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 barrier, but its role has not been investigated due embryonic lethality animal models genetic modification components endothelium. Objective: To determine effects aberrant activation underlying molecular mechanisms. Methods Results: We established ZEG-NICD1 (notch1 intracellular domain)/Tie2-tTA/Tet-O-Cre transgenic mouse model constitutively activate Notch1 endothelial cells adult mice. triple mice developed severe albuminuria significantly decreased VE-cadherin (vascular cadherin) expression In vitro studies showed that either NICD1 (Notch1 domain) lentiviral infection or treatment ligand DLL4 (delta-like 4) markedly reduced increased monolayer permeability human renal cells. addition, gene knockdown glycocalyx. Further investigation demonstrated activated suppression was through transcription factors SNAI1 (snail family transcriptional repressor 1) ERG (Ets related gene), which bind ?373 E-box ?134/?118 ETS (E26 transformation-specific) element promoter, respectively. Conclusions: Our results reveal novel regulatory mechanisms whereby dictates level ERG, leading dysfunction barrier induction albuminuria. Graphic Abstract: A graphic abstract available for this article.