Podocyte Vps34 deficiency drives early-onset glomerulopathy and mesangial IgA-dominant immune-complex deposition: a novel mouse model linking vesicular trafficking to glomerular immune dysregulation.

BACKGROUND: Podocytes are indispensable for maintaining glomerular filtration barrier integrity and immune homeostasis. Although vacuolar protein sorting 34 (Vps34), a class III phosphoinositide 3-kinase, orchestrates intracellular membrane trafficking, its roles in glomerular immune regulation remain incompletely defined. This study identifies a critical link between podocyte-specific Vps34 dysfunction and glomerular immune injury, characterized by pronounced mesangial IgA deposition. METHODS: A podocyte-selective Vps34 knockout mouse model was generated. Kidney architecture and function were systematically assessed using histological, immunofluorescent, and ultrastructural analyses. Systemic immunoglobulin concentrations were measured, and bulk renal transcriptomics were conducted to delineate molecular alterations. RESULTS: Selective deletion of Vps34 in podocytes induced rapid-onset proteinuria from three weeks of age, progressive renal failure, and early mortality (median survival nine weeks). These mice exhibited marked mesangial expansion, focal and global glomerulosclerosis, and widespread foot process effacement. Immunofluorescence revealed intense mesangial IgA deposition, accompanied by elevated serum IgA and IgM and reduced IgG levels. Comprehensive transcriptomic profiling revealed progressive immune-related transcriptional changes, highlighting upregulation of antigen presentation, B cell activation, cytokine signaling, and extracellular matrix remodeling. In addition, Vps34 deficiency was associated with increased expression of DAMP-associated and inflammasome-related genes, suggesting engagement of inflammation-related transcriptional programs within the injured kidney. CONCLUSIONS: Podocyte-specific Vps34 deficiency leads to progressive podocyte injury accompanied by IgA-dominant immune-complex deposition and immune-related changes in the kidney. These findings reveal an association between podocyte dysfunction and glomerular immune abnormalities and suggest a potential role of vesicular trafficking defects in immune dysregulation during proteinuric kidney disease.