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 language | English |
|---|---|
| Article number | e2005233 |
| Journal | PLoS Biology |
| Volume | 16 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 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)
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}
Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming. / Huang, Shizheng; Park, Jihwan; Qiu, Chengxiang; Chung, Ki Wung; Li, Szu Yuan; Sirin, Yasemin; Han, Seung Hyeok; Taylor, Verdon; Zimber-Strobl, Ursula; Susztak, Katalin.
In: PLoS Biology, Vol. 16, No. 9, e2005233, 09.2018.Research output: Contribution to journal › Article
TY - JOUR
T1 - Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming
AU - Huang, Shizheng
AU - Park, Jihwan
AU - Qiu, Chengxiang
AU - Chung, Ki Wung
AU - Li, Szu Yuan
AU - Sirin, Yasemin
AU - Han, Seung Hyeok
AU - Taylor, Verdon
AU - Zimber-Strobl, Ursula
AU - Susztak, Katalin
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054821089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054821089&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.2005233
DO - 10.1371/journal.pbio.2005233
M3 - Article
C2 - 30226866
AN - SCOPUS:85054821089
VL - 16
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 9
M1 - e2005233
ER -