The important roles and molecular mechanisms of annexin A(2) autoantibody in children with nephrotic syndrome

BACKGROUND: In recent years, B-cell dysfunction has been found to play an important role in the pathogenesis of primary nephrotic syndrome (PNS). B cells play a pathogenic role by secreting antibodies against their target antigens after transforming into plasma cells. Therefore, this study aimed to screen the autoantibodies that cause PNS and explore their pathogenic mechanisms. METHODS: Western blotting and mass spectrometry were employed to screen and identify autoantibodies against podocytes in children with PNS. Both in vivo and in vitro experiments were used to study the pathogenic mechanism of PNS. The results were confirmed in a large multicenter clinical study in children. RESULTS: Annexin A(2) autoantibody was highly expressed in children with PNS with a pathological type of minimal change disease (MCD) or focal segmental glomerulosclerosis without genetic factors. The mouse model showed that anti-Annexin A(2) antibody could induce proteinuria in vivo. Mechanistically, the effect of Annexin A(2) antibody on the Rho signaling pathway was realized through promoting the phosphorylation of Annexin A(2) at Tyr24 on podocytes by reducing its binding to PTP1B, which led to the cytoskeletal rearrangement and damage of podocytes, eventually causing proteinuria and PNS. CONCLUSIONS: Annexin A(2) autoantibody may be responsible for some cases of PNS with MCD/FSGS in children.