Notch Blockade Specifically in Bone Marrow-Derived FSP-1-Positive Cells Ameliorates Renal Fibrosis

Background: The infiltration of inflammatory cells during a kidney injury stimulates myofibroblast activation leading to kidney fibrosis. Fibroblast-specific protein 1 (FSP-1) positive cells have been reported as either myofibroblasts or monocytes during tissue fibrosis. The functions of FSP-1⁺ cells that are associated with the development of renal fibrosis and the signaling pathways that regulate FSP-1⁺ cell activation have not been well defined.

Methods: In mice with unilateral ureteral obstruction (UUO), we characterized FSP-1⁺ cells and determined the role of the Notch signaling pathway in the activation of bone marrow-derived FSP-1⁺ cells during kidney fibrosis.

Results: In kidneys from mice with UUO, the FSP-1⁺ cells accumulated significantly in the tubulointerstitial area. By using immunostaining and FSP-1 reporter mice, we found that FSP-1 was co-stained with inflammatory cell markers, but not myofibroblast markers. Results from mice with bone marrow transplantations showed that FSP-1⁺ cells in obstructed kidneys represent a bone marrow-derived population of inflammatory cells. In cultured FSP-1⁺ cells, the inhibition of Notch signaling suppressed the activation and cytokine secretion of FSP-1⁺ cells that were induced by LPS but not by IL-4. The specific KO or blockade of Notch signaling in bone marrow-derived FSP-1⁺ cells suppressed UUO-induced ECM deposition, the infiltration of FSP-1⁺ inflammatory cells, and cytokine production. These responses ameliorated myofibroblast accumulation and renal fibrosis in obstructed kidneys.

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