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01-05-2018 | Original Paper

Glomerular endothelial cell maturation depends on ADAM10, a key regulator of Notch signaling

Authors: Gregory Farber, Romulo Hurtado, Sarah Loh, Sébastien Monette, James Mtui, Raphael Kopan, Susan Quaggin, Catherine Meyer-Schwesinger, Doris Herzlinger, Rizaldy P. Scott, Carl P. Blobel

Published in: Angiogenesis | Issue 2/2018

Abstract

The principal function of glomeruli is to filter blood through a highly specialized filtration barrier consisting of a fenestrated endothelium, the glomerular basement membrane and podocyte foot processes. Previous studies have uncovered a crucial role of endothelial a disintegrin and metalloprotease 10 (ADAM10) and Notch signaling in the development of glomeruli, yet the resulting defects have not been further characterized nor understood in the context of kidney development. Here, we used several different experimental approaches to analyze the kidneys and glomeruli from mice lacking ADAM10 in endothelial cells (A10ΔEC mice). Scanning electron microscopy of glomerular casts demonstrated enlarged vascular diameter and increased intussusceptive events in A10ΔEC glomeruli compared to controls. Consistent with these findings, genes known to regulate vessel caliber (Apln, AplnR and Vegfr3) are significantly upregulated in A10ΔEC glomeruli. Moreover, transmission electron microscopy revealed the persistence of diaphragms in the fenestrae of A10ΔEC glomerular endothelial cells, which was corroborated by the elevated expression of the protein PLVAP/PV-1, an integral component of fenestral diaphragms. Analysis of gross renal vasculature by light sheet microscopy showed no major alteration of the branching pattern, indicating a localized importance of ADAM10 in the glomerular endothelium. Since intussusceptions and fenestrae with diaphragms are normally found in developing, but not mature glomeruli, our results provide the first evidence for a crucial role of endothelial ADAM10, a key regulator of Notch signaling, in promoting the development and maturation of the glomerular vasculature.

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Title: Glomerular endothelial cell maturation depends on ADAM10, a key regulator of Notch signaling
Authors: Gregory Farber
Romulo Hurtado
Sarah Loh
Sébastien Monette
James Mtui
Raphael Kopan
Susan Quaggin
Catherine Meyer-Schwesinger
Doris Herzlinger
Rizaldy P. Scott
Carl P. Blobel
Publication date: 01-05-2018
Publisher: Springer Netherlands
Published in: Angiogenesis / Issue 2/2018
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-018-9599-4

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