<b>GAS6/AXL signaling pathway contributes to PLA2R overexpression in membranous nephropathy</b>

Phospholipase A2 receptor, PLA2R, is the most frequently targeted auto-antigen in membranous nephropathy(MN).However, the precise mechanisms PLA2R plays in the development and progression of the disease remain to be elucidated. From the microarray data ofthe NEPTUNE study, we found that AXL, a tyrosine protein kinase receptor,was expressed and elevatedin podocytesin patients with MN . We used in situ hybridization,immunofluorescence and immunogold analysesand provided direct evidences that AXL was localized in podocytes and elevated in renal biopsies from patients wtih MN. Furthermore, the ELISA and immunohistochemical analysesrevealed that the expression level of AXL was enhanced and correlated with poor renal outcomes in patients with MN. Notably, upon the stimulation with GAS6, the ligand of AXL, the level of PLA2R was upregulated in cultured human podocytesin vitrodue to delayed degradation while the knockout of AXL reversed the effect. Last, co-immunoprecipitationand Bio-Layer Interferometry analysesdemonstrated that AXL interacted directly withPLA2R. In conclusion, the present study shows that AXLis localized in podocytes and the increase in membranous nephropathy is correlated with the level of PLA2R. AXL could be used as a biomarker in the pathogenesis of membranous nephropathy.