Kidney Week

Abstract: FR-OR106

Renal Tubular-Specific Jagged1 Deletion Ameliorates Kidney Fibrosis via Mitochondrial Transcription Factor A (TFAM) Regulation and Metabolic Reprogramming

Session Information

• Stress Signaling and Fibrosis
  November 03, 2017 | Location: Room 277, Morial Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Cell Biology

• 204 Extracellular Matrix Biology, Fibrosis, Cell Adhesion

Authors

• Huang, Shizheng, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Shizheng Huang, PhD

• Park, Jihwan, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Jihwan Park,

• Qiu, Chengxiang, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Chengxiang Qiu,

• Li, Szu-Yuan, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Szu-Yuan Li,

• Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States

Katalin Susztak,

Background

Notch is a basic cell-cell communication pathway where expression of the ligand, Jagged1,2 or Delta1,3,4 on signal-sending cells, Notch1-4 on the signal-receiving cell. Our group previously established that tubular epithelial cell (TEC) Notch signaling plays a key role in kidney fibrosis development. However, the precise ligand and receptor pairs that contribute to kidney fibrosis still remain unknown. Here we performed a systematic analysis to define the specific ligands and molecular pathways of Notch-induced fibrosis development in TEC.

Methods

To examine Notch ligands and receptors expression profiles, we used genome wide gene expression arrays from well phenotyped microdissected human kidney tubule samples (n=94). Mechanistic studies were performed by generating mice with tubule-specific deletion of Jagged1 (Ksp^cre/Jagged1^flox/flox). Kidney injury was induced by administering folic acid (FA) intraperitoneally. In vitro studies were performed using a co-culture system of rat tubule epithelial cells (NRK52E) and mouse stromal cells that express Jagged1. Direct targets of Notch signaling were identified by ChIP-Seq with co-transcription factor Rbpj.

Results

In microdissected human kidney tissue samples, of the ligands, Jagged1 showed the best correlation with the degree of interstitial fibrosis. Increased Jagged1 expression was recapitulated in the FA-induced kidney fibrosis model and in primary cultured TEC treated with TGFB1. Mice with tubule specific deletion of Jagged1 mice showed no kidney specific alterations at baseline, but were protected from FA-induced kidney fibrosis. There was marked reduction in inflammatory and profibrotic gene expression and improvement of histology in the Jagged1 knock-out mice following FA injection. In vitro co-culture studies indicated that Jagged1 expression induces proliferation and dedifferentiation of TEC. We found that mitochondrial transcription factor A (TFAM) is a direct target gene for Notch signaling by ChIP-seq. Expression of TFAM could rescue the metabolic defect and protect from Jagged1-induced fibrosis development in co-culture system.

Conclusion

The effect of Notch in TEC induced fibrosis development is mediated by Jagged1. Jagged1 induces epithelial dedifferentiation and fibrosis via TFAM mediated metabolic reprogramming.

Funding

• NIDDK Support