PT - JOURNAL ARTICLE AU - Shizheng Huang AU - Jihwan Park AU - Chengxiang Qiu AU - Yasemin Sirin AU - Seung Hyeok Han AU - Szu-yuan Li AU - Verdon Taylor AU - Ursula Zimber-Strobl AU - Katalin Susztak TI - <em>Jagged1/Notch2</em> Controls Kidney Fibrosis via <em>Tfam</em>-mediated Metabolic Reprogramming AID - 10.1101/285726 DP - 2018 Jan 01 TA - bioRxiv PG - 285726 4099 - http://biorxiv.org/content/early/2018/03/29/285726.short 4100 - http://biorxiv.org/content/early/2018/03/29/285726.full 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. RNA sequencing analysis of kidneys of mice with folic acid 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 perinatal lethality.In summary, Jag1/Notch2 plays a key role in kidney fibrosis development by regulating Tfam expression and metabolic reprogramming.