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

Shizheng Huang, Jihwan Park, Chengxiang Qiu, Ki Wung Chung, Szu Yuan Li, Yasemin Sirin, Seung Hyeok Han, Verdon Taylor, Ursula Zimber-Strobl, Katalin Susztak

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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 (Ksp cre /Jag1 flox/flox and Ksp cre /Notch2 flox/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.

Original languageEnglish
Article numbere2005233
JournalPLoS Biology
Volume16
Issue number9
DOIs
Publication statusPublished - 2018 Sep

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All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Huang, S., Park, J., Qiu, C., Chung, K. W., Li, S. Y., Sirin, Y., Han, S. H., Taylor, V., Zimber-Strobl, U., & Susztak, K. (2018). Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. PLoS Biology, 16(9), [e2005233]. https://doi.org/10.1371/journal.pbio.2005233