Autoantibodies Targeting Vinculin Reveal Novel Insight into the Mechanisms of Autoimmune Podocytopathies

<b>Background:</b> Emerging evidence suggests that autoantibodies targeting podocytes are potential contributors to idiopathic nephrotic syndrome (INS); however, the specific mechanisms remain unclear. This study aims to explore the pathogenic role and underlying mechanisms of anti-vinculin autoantibodies in INS. <b>Methods:</b> Serum anti-vinculin autoantibody levels detected by protein microarray and clinical data were compared among INS patients (<i>n</i> = 147), healthy individuals (<i>n</i> = 84), and patients with other kidney or immune diseases (<i>n</i> = 100 of each disease). Immune-mediated mouse models were established to verify the pathogenicity of anti-vinculin autoantibodies. Mouse urine was monitored for urine protein levels, while immunofluorescence, pathological staining, and electron microscopy assessed kidney pathological and ultrastructural changes. Transcriptome sequencing of mouse kidney tissues was performed to investigate the key molecular mechanisms and signaling pathways involved in kidney injury post-immunization. <b>Results:</b> Anti-vinculin autoantibody levels were specifically elevated in INS patients, with a 54.42% positivity rate, correlating with urinary albumin, serum albumin, cholesterol, and CD19 levels. The average anti-vinculin autoantibody levels dropped markedly in pediatric INS patients during remission. Mouse experiments revealed that injecting anti-vinculin antibodies or recombinant vinculin protein induced proteinuria and podocyte injury in the immunized mice, and the renal phenotype closely resembled the pathological characteristics of minimal change disease. Transcriptome sequencing of renal tissues revealed up-regulation of inflammation, immune responses, cytokine activities, and B cell activation pathways in the immunized mice, while cytoskeleton-related functions were down-regulated. <b>Conclusions:</b> Autoantibodies targeting vinculin act as pathogenic autoantibodies in INS and hold potential value for diagnosing and monitoring INS progression.