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

doi:10.1371/journal.pbio.2005233

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

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

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	https://doi.org/10.1371/journal.pbio.2005233
Publication status	Published - 2018 Sep

Bibliographical note

Funding Information:
NIH (grant number DK076077). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number DK087635). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number DK1088220). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Juvenile Diabetes Research Foundation (grant number 2-SRA-2014-278-Q-R). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number P30-DK050306). Received by Molecular Pathology and Imaging Core at University of Pennsylvania. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number P30-DK19525). Received by Diabetes Research Center at University of Pennsylvania. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. Pamela Stanley from Albert Einstein College of Medicine for providing L cells and JAG1-expressing L cells. The authors thank Frank Chinga and Antje Gruenwald for assistance with animal breeding and care. The authors thank Joshua S. Bryer for proofreading.

Publisher Copyright:
© 2018 Huang et al. http://creativecommons.org/licenses/by/4.0/.

All Science Journal Classification (ASJC) codes

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

UN SDGs

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title = "Jagged1/Notch2 controls kidney fibrosis via Tfam-mediated metabolic reprogramming",

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. ",

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

note = "Funding Information: NIH (grant number DK076077). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number DK087635). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number DK1088220). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Juvenile Diabetes Research Foundation (grant number 2-SRA-2014-278-Q-R). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number P30-DK050306). Received by Molecular Pathology and Imaging Core at University of Pennsylvania. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number P30-DK19525). Received by Diabetes Research Center at University of Pennsylvania. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. Pamela Stanley from Albert Einstein College of Medicine for providing L cells and JAG1-expressing L cells. The authors thank Frank Chinga and Antje Gruenwald for assistance with animal breeding and care. The authors thank Joshua S. Bryer for proofreading. Publisher Copyright: {\textcopyright} 2018 Huang et al. http://creativecommons.org/licenses/by/4.0/.",

year = "2018",

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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 › peer-review

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AU - Sirin, Yasemin

AU - Han, Seung Hyeok

AU - Taylor, Verdon

AU - Zimber-Strobl, Ursula

AU - Susztak, Katalin

N1 - Funding Information: NIH (grant number DK076077). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number DK087635). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number DK1088220). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Juvenile Diabetes Research Foundation (grant number 2-SRA-2014-278-Q-R). Received by K.S. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number P30-DK050306). Received by Molecular Pathology and Imaging Core at University of Pennsylvania. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number P30-DK19525). Received by Diabetes Research Center at University of Pennsylvania. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Dr. Pamela Stanley from Albert Einstein College of Medicine for providing L cells and JAG1-expressing L cells. The authors thank Frank Chinga and Antje Gruenwald for assistance with animal breeding and care. The authors thank Joshua S. Bryer for proofreading. Publisher Copyright: © 2018 Huang et al. http://creativecommons.org/licenses/by/4.0/.

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.

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

Abstract

Bibliographical note

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UN SDGs

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