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Activation of Notch2 signaling drives cyst growth in kidney [RNA-seq: R26NICD2 Pax-rtTA]

ABSTRACT: Activation of Notch2 signaling drives cyst growth in kidney [RNA-seq: R26NICD2 Pax-rtTA]

PROVIDER: PRJNA953775 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24112612_1.fastq.gz	Fastqsanger.gz
	SRR24112612_2.fastq.gz	Fastqsanger.gz
	SRR24112613_1.fastq.gz	Fastqsanger.gz
	SRR24112613_2.fastq.gz	Fastqsanger.gz
	SRR24112614_1.fastq.gz	Fastqsanger.gz

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Activation of Notch2 signaling drives cyst growth in kidney [RNA-seq: R26NICD2 Pax-rtTA]

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

Project description: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-induced nephropathy, unilateral ureteral obstruction, or 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 folic acid induced kidney fibrosis. Tubule-specific genetic deletion of Notch1 and global knock-out 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. Kidney tubule specific deletion of Tfam resulted in fibrosis. In summary, Jag1/Notch2 plays a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.

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Activation of Notch2 signaling drives cyst growth in kidney [RNA-seq: R26NICD2 KspCre]

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NOTCH2 mutants

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