Targeted γ-secretase inhibition of Notch signaling activation in acute renal injury.

Détails

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Etat: Serval
Version: Author's accepted manuscript
ID Serval
serval:BIB_C1BB88B05E11
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Targeted γ-secretase inhibition of Notch signaling activation in acute renal injury.
Périodique
American journal of physiology. Renal physiology
Auteur(s)
Wyss J.C., Kumar R., Mikulic J., Schneider M., Aebi J.D., Juillerat-Jeanneret L., Golshayan D.
ISSN
1522-1466 (Electronic)
ISSN-L
1522-1466
Statut éditorial
Publié
Date de publication
01/05/2018
Peer-reviewed
Oui
Volume
314
Numéro
5
Pages
F736-F746
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
The Notch pathway has been reported to control tissue damage in acute kidney diseases. To investigate potential beneficial nephroprotective effects of targeting Notch, we developed chemically functionalized γ-secretase inhibitors (GSIs) targeting γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT), two enzymes overexpressed in the injured kidney, and evaluated them in in vivo murine models of acute tubular and glomerular damage. Exposure of the animals to disease-inducing drugs together with the functionalized GSIs improved proteinuria and, to some extent, kidney dysfunction. The expression of genes involved in the Notch pathway, acute inflammatory stress responses, and the renin-angiotensin system was enhanced in injured kidneys, which could be downregulated upon administration of functionalized GSIs. Immunohistochemistry staining and Western blots demonstrated enhanced activation of Notch1 as detected by its cleaved active intracellular domain during acute kidney injury, and this was downregulated by concomitant treatment with the functionalized GSIs. Thus targeted γ-secretase-based prodrugs developed as substrates for γ-GT/γ-GCT have the potential to selectively control Notch activation in kidney diseases with subsequent regulation of the inflammatory stress response and the renin-angiotensin pathways.
Mots-clé
Notch, acute kidney injury, drug-targeting, inflammation, γ-secretase inhibitors, aminopeptidase A, kidney diseases, renin-angiotensin, γ-GT, γ-glutamyltranspeptidase
Pubmed
Web of science
Création de la notice
09/10/2017 13:49
Dernière modification de la notice
27/08/2018 18:17
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