Home
Deutsch
Advanced Search
Browse by ...
Publication overview
Contact persons
Help
Publ. Version/Full Text
Postprint
DOI
PMC
 |
Open Access Gold |
|
as soon as is submitted to ZB.
Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming.
PLoS Biol. 16:e2005233 (2018)
While Notch signaling has been proposed to play a key role in fibrosis, the direct molecular pathways targeted by Notch signaling and the precise ligand and receptor pair that are responsible for kidney disease remain poorly defined. In this study, we found that JAG1 and NOTCH2 showed the strongest correlation with the degree of interstitial fibrosis in a genome-wide expression analysis of a large cohort of human kidney samples. Transcript analysis of mouse kidney disease models, including folic-acid (FA)–induced nephropathy, unilateral ureteral obstruction (UUO), or apolipoprotein L1 (APOL1)-associated kidney disease, indicated that Jag1 and Notch2 levels were higher in all analyzed kidney fibrosis models. Mice with tubule-specific deletion of Jag1 or Notch2 (Kspcre/Jag1flox/floxand Kspcre/Notch2flox/flox) had no kidney-specific alterations at baseline but showed protection from FA-induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knockout of Notch3 had no effect on fibrosis. In vitro chromatin immunoprecipitation experiments and genome-wide expression studies identified the mitochondrial transcription factor A (Tfam) as a direct Notch target. Re-expression of Tfam in tubule cells prevented Notch-induced metabolic and profibrotic reprogramming. Tubule–specific deletion of Tfam resulted in fibrosis. In summary, Jag1 and Notch2 play a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.
Altmetric
Additional Metrics?
Edit extra informations
Login
Publication type
Article: Journal article
Document type
Scientific Article
Keywords
To-mesenchymal Transition; Intestinal Epithelial-cells; Notch Signaling Pathway; Diabetic-nephropathy; Renal Fibrosis; Interstitial Fibrosis; Disease; Activation; Expression; Mice
ISSN (print) / ISBN
1544-9173
e-ISSN
1545-7885
Journal
PLoS Biology
Quellenangaben
Volume: 16,
Issue: 9,
Article Number: e2005233
Publisher
Public Library of Science (PLoS)
Publishing Place
1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Research Unit Gene Vector (AGV)