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PLoS Biol. 2018 Sep 18;16(9):e2005233. doi: 10.1371/journal.pbio.2005233. eCollection 2018 Sep.

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

Author information

1
Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
2
Department of Biomedicine, University of Basel, Basel, Switzerland.
3
Research Unit Gene Vectors, Helmholtz Zentrum München, German Research Center for Environment and Health, Munich, Germany.

Abstract

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/flox and 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.

PMID:
30226866
PMCID:
PMC6161902
DOI:
10.1371/journal.pbio.2005233
[Indexed for MEDLINE]
Free PMC Article

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