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

Autor: Chengxiang Qiu, Jihwan Park, Ki Wung Chung, Szu Yuan Li, Yasemin Sirin, Shizheng Huang, Verdon Taylor, Ursula Zimber-Strobl, Seung Hyeok Han, Katalin Susztak
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
030232 urology & nephrology
Gene Expression
Kidney
Biochemistry
0302 clinical medicine
Cell Signaling
Fibrosis
Chronic Kidney Disease
Medicine and Health Sciences
Receptor
Notch2
Biology (General)
Energy-Producing Organelles
Notch Signaling
Mice
Knockout
General Neuroscience
High Mobility Group Proteins
Animal Models
3. Good health
Mitochondria
DNA-Binding Proteins
Kidney Tubules
Experimental Organism Systems
Nephrology
Anatomy
Cellular Structures and Organelles
General Agricultural and Biological Sciences
Research Article
Signal Transduction
JAG1
Genotype
QH301-705.5
Notch signaling pathway
Mouse Models
Biology
Bioenergetics
Research and Analysis Methods
Models
Biological
General Biochemistry
Genetics and Molecular Biology
Nephropathy
Mitochondrial Proteins
03 medical and health sciences
Model Organisms
medicine
Genetics
Animals
Humans
Gene Regulation
RNA
Messenger
Transcription factor
Cell Proliferation
General Immunology and Microbiology
Kidney metabolism
Biology and Life Sciences
Proteins
Kidneys
Epithelial Cells
Renal System
Cell Biology
TFAM
Cell Dedifferentiation
medicine.disease
Regulatory Proteins
Rats
Mice
Inbred C57BL
030104 developmental biology
Gene Ontology
Cancer research
Jagged-1 Protein
Kidney disease
Developmental Biology
Transcription Factors
Zdroj: PLoS Biology, Vol 16, Iss 9, p e2005233 (2018)
PLoS Biology
PLoS Biol. 16:e2005233 (2018)
ISSN: 1545-7885
1544-9173
Popis: 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.
Author summary Chronic kidney disease (CKD) is the ninth leading cause of death in the United States. Kidney fibrosis usually occurs at the final stage of the disease. The Notch signaling pathway is a cell–cell communication pathway, that activated by a ligand (expressed on the signal-sending cell) interacting with and inducing the breakdown of the Notch receptor on the receiving cell. We previously established that Notch signaling in renal tubular epithelial cells (RTECs) plays a key role in kidney fibrosis development. However, the precise ligand and receptor pair that contributes to kidney fibrosis remain unknown. Here, we performed a systematic analysis to define the specific molecular pathways of Notch-induced fibrosis development in RTECs. We found that Jag1 acting together with Notch2 leads to metabolic reprogramming of RTECs via mitochondrial transcription factor A (Tfam), resulting in cell proliferation and dedifferentiation and fibrosis development. Our study suggests that targeting JAG1 or NOTCH2 may have important therapeutic potential for treatment of CKD.
Databáze: OpenAIRE
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