Endothelial AGGF1 contributes to glomerular barrier dysfunction via TNFSF12/FN14-Src-VE-cadherin signaling in diabetic kidney disease

Disruption of the glomerular filtration barrier (GFB) is a key feature of diabetic kidney disease (DKD), but the underlying mechanisms remain incompletely understood. We investigated the role of angiogenic factor 1 (AGGF1) in glomerular endothelial barrier dysfunction in DKD. AGGF1 expression was examined in kidney samples from patients with DKD and in db/db mice. We also used endothelial cell-specific Aggf1 knockout mice and in vitro endothelial cell experiments to assess the effects of AGGF1 on vascular leakage and endothelial junctions. AGGF1 expression was increased in kidneys from patients with DKD and db/db mice. Endothelial Aggf1 deletion reduced vascular leakage in diabetic mice. Mechanistically, AGGF1 promoted Src-dependent VE-cadherin phosphorylation and dissociation of the VE-cadherin/β-catenin complex. Semaglutide treatment was associated with reduced renal AGGF1 expression and improved endothelial barrier-related outcomes in db/db mice. In vitro, AGGF1 overexpression attenuated the beneficial effect of semaglutide on endothelial junctional proteins under high-glucose conditions. Together, these findings identify endothelial AGGF1 as a contributor to GFB dysfunction in DKD and suggest that it may be a potential therapeutic target.