NF-κB-driven lymphangiogenesis affects kidney function via a VEGFR-3-mediated pathway.

The lymphatic system maintains fluid homeostasis and orchestrates immune cell trafficking throughout tissues. While extensively studied in cancer and lymphedema, its role in nonlymphoid organs, particularly the kidney, remains an emerging area of investigation. Previous research established molecular connections among NF-κB, VEGFR-3, and PROX-1 in regulating lymphatic growth during inflammation, and studies using global knockout mice revealed that the NF-κB1 subunit (p50) influences lymphatic vessel density. However, the role of RelA - a key component of the canonical NF-κB heterodimer - in regulating lymphatic growth and kidney function following acute kidney injury (AKI) remains unexplored. Using an inducible, predominantly lymphatic endothelial cell-specific RelA-knockout mouse model, we demonstrated that RelA expression in VEGFR-3+ cells is essential for VEGFR-3-driven lymphangiogenesis following AKI. Knockout mice exhibited substantially worse kidney function, altered histological features, impaired VEGFR-3-dependent lymphangiogenesis, and dysregulated immune cell trafficking compared with WT mice. Compensatory upregulation of PROX-1 and podoplanin occurred despite decreased VEGFR-3 and LYVE-1 total protein expression, suggesting complex regulatory mechanisms. Our findings suggest that RelA is a critical sensor for inflammation and regulator of protective lymphangiogenesis following kidney injury and provide insights into potential therapeutic targets for improved kidney injury outcomes.