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Abstract: FR-OR27

Notch Blockade Specifically in FSP-1-Positive Cells Ameliorates Renal Fibrosis by Attenuating Inflammation

Session Information

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Cheng, Jizhong, Baylor College of Medicine, Houston, Texas, United States
  • Liang, Ming, Baylor College of Medicine, Houston, Texas, United States
  • Wu, Yongdong, Baylor College of Medicine, Houston, Texas, United States
  • Lee, Tae Hoon, Baylor College of Medicine, Houston, Texas, United States
  • Mitch, William E., Baylor College of Medicine, Houston, Texas, United States
  • Truong, Luan D., Houston Methodist, Houston, Texas, United States
Background

The infiltration of inflammatory cells during kidney injury stimulates myofibroblast activation leading to kidney fibrosis. Fibroblast specific protein 1 (FSP-1) positive cells have been reported as myofibroblast and monocytes during tissue fibrosis. The function and regulation of the FSP-1+ cells have not been well investigated.

Methods

In current study, the FSP-1+ cells were characterized and the role of Notch signaling in activation of these cells was determined during kidney fibrosis.

Results

After creating unilateral ureteral obstruction (UUO), the FSP-1+ cells were significantly accumulated in the tubulointerstitial area. Only few FSP-1+ cells (< 5%) expressed markers of myofibroblasts, in contrast, most of the FSP-1+ cells costained with inflammatory cell markers (CD45, F4/80). This observation was further confirmed obstructed kidneys in FSP-1 reporter mice (FSP-1-GFP). Most of GFP+ cells (FSP-1+ cells, > 90%) were positive for myeloid cell marker. Moreover, these GFP+ cells were found in obstructed kidneys in WT mice that were transplanted with bone marrow from FSP-1-GFP reporter mice. These results indicate that FSP-1+ cells represent a bone marrow-derived specific inflammatory cell population. Notably, the levels of Notch targets were increased in UUO, and activated Notch1 co-expressed with FSP-1 in cells in tubulointerstitium. In vitro, the isolated bone marrow FSP-1+ cells were differentiated into functional type I and type II macrophage after treatment with LPS or IL-4, respectively. Inhibition of Notch signaling blocked activation and cytokine secretion of FSP-1+ cells that were induced by LPS, but not by IL-4. In mice, specific KO of RBP-Jk in bone marrow FSP-1+ cells suppressed UUO-induced ECM deposition, inflammatory cell accumulation, cytokine production, and interstitial fibrosis. Furthermore, inducible expression of dominant negative mastermind1, the co-activator of Notch signaling, in FSP-1+ cells ameliorated myofibroblast activation and renal fibrosis in obstructed kidneys.

Conclusion

In conclusion, our study reveals that most of FSP-1+ cells in obstructed kidneys are activated macrophage that are derived from bone marrow, Notch signaling activates the production of M1 cytokines in FSP-1+ monocytes/macrophage, which is important for renal inflammation and fibrosis.

Funding

  • NIDDK Support