PuSH - Publication Server of Helmholtz Zentrum München

Huang, S.* ; Park, J.* ; Qiu, C.* ; Chung, K.F.* ; Li, S.Y.* ; Sirin, Y.* ; Han, S.H.* ; Taylor, V.* ; Zimber-Strobl, U. ; Susztak, K.*

Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming.

PLoS Biol. 16:e2005233 (2018)
Publ. Version/Full Text Postprint DOI
Open Access Gold
Creative Commons Lizenzvertrag
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, Pages: , Article Number: e2005233 Supplement: ,
Publisher Public Library of Science (PLoS)
Publishing Place 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Reviewing status Peer reviewed