EphrinB2 Ameliorates Renal Fibrosis by Inhibiting the TGF-β/Smad3 Signaling Pathway and the Inflammation Response.

Background: EphrinB2 is known to play a variety of roles in the pathological process of fibrosis in the heart, skin, and retina, according to current research. However, the role of Ephrin- B2 in renal fibrosis remains to be clarified.

Objective: We aimed to investigate the role of EphrinB2 in the renal fibrosis model and its underlying mechanisms.

Materials and methods: Unilateral ureteral obstruction (UUO) models and TGF-β-treated renal tubular epithelial cells (HK2) were adopted in this study to determine if EphrinB2 could lead to renal fibrosis.

Results: EphrinB2 was highly expressed in renal tubular cells in UUO mice. Using adeno-associated virus (AAV)-mediated EphrinB2 overexpression, we observed significant improvements in renal function and injury, as well as a marked reduction in fibrosis. For example, EphrinB2 overexpression decreased the expression of fibrosis markers such as Fibronectin and α-SMA by approximately 40%. In vitro, EphrinB2 also significantly reduced extracellular matrix (ECM) deposition and cellular fibrosis under TGF-β stimulation. Mechanistically, EphrinB2 inhibited TGF-β/Smad3 signaling by approximately 40%, and reduced inflammatory markers such as MCP1 and IL-1β by approximately 60% and 35%, respectively.

Conclusions: This study uncovered a previously unrecognized anti-fibrotic role of EphrinB2 in renal fibrosis, which is achieved through the prevention TGF-β/Smad3 signaling and inflammation response. It seemed that EphrinB2 might be a promising therapeutic target in the treatment of fibrotic diseases and kidney failure.