Platelet glycoprotein VI promotes folic acid-induced acute kidney injury through interaction with tubular epithelial cell-derived galectin-3.

BACKGROUND

Acute kidney injury (AKI) is defined by a significant reduction in renal function, which subsequently impairs coagulation and activates the inflammatory immune response, ultimately resulting in damage to renal tubular epithelial cells (TECs). Platelets are crucial in mediating both inflammatory and coagulation processes. While it is established that platelet activation contributes to the progression of AKI, the precise mechanisms underlying this relationship remain largely unclear.

METHODS

We investigated platelet function in folic acid-induced acute kidney injury (FA-AKI) and examined the effects of galectin-3, a protein derived from renal tubular epithelial cells (TECs), on its interaction with platelet glycoprotein VI (GPVI). This interaction was assessed through the analysis of monocyte migration, macrophage polarization, and the generation of monocyte-platelet aggregation. Additionally, we utilized platelet GPVI-specific knockout mice in conjunction with TD139, a small-molecule inhibitor of galectin-3, to explore the effects of inhibiting the galectin-3-GPVI interaction on FA-AKI.

RESULTS

In the current study, we observed that mouse platelets displayed hyperactivity in the context of functional acute kidney injury (FA-AKI). This hyperactivity was linked to the interaction between galectin-3, which is derived from damaged renal tubular epithelial cells (TECs), and the glycoprotein VI (GPVI) on platelets. Our findings indicated a heightened interaction between activated platelets and monocytes, along with an increase in monocyte-platelet aggregation (MPA) within the circulation. The increased infiltration of monocytes and platelets in renal tissue was further validated through CD41 and CD68 immunofluorescence techniques. Additionally, the interaction between galectin-3 and platelet GPVI was shown to facilitate monocyte migration, promote M1-type macrophage polarization, and enhance phagocytic activity. The galectin-3 inhibitor TD139 significantly suppressed monocyte-platelet aggregation (MPA), reduced inflammatory responses, and extended the survival of mice with acute kidney injury (AKI).

CONCLUSIONS

These findings suggest that galectin-3, which is released from damaged cells during acute kidney injury (AKI), exacerbates renal inflammation and tissue damage by activating platelets through glycoprotein VI (GPVI). This activation enhances interactions between monocytes and platelets, ultimately leading to the formation of monocyte-platelet aggregates (MPA) and the polarization of M1 macrophages.