Interplay of HIF-1α, SMAD2, and VEGF signaling in hypoxic renal environments: impact on macrophage polarization and renoprotection

This study investigates the roles of hypoxia-inducible factor (HIF-1α), SMAD2, and vascular endothelial growth factor (VEGF) in renal repair under hypoxic conditions, focusing on their impact on macrophage phenotype transformation. Bioinformatics analysis identified SMAD2 as a key gene in renal injury, correlating with HIF-1α and VEGF levels. In a cohort of 60 pediatric patients, non-AKI individuals exhibited higher VEGF and SMAD2 levels but lower HIF-1α compared to AKI patients. Using a chronic hypoxia rat model, bevacizumab treatment exacerbated renal damage, as indicated by elevated serum creatinine (79.4 ± 61.7 μmol/L), increased inflammatory markers, and heightened HIF-1α expression. Bevacizumab's inhibition of VEGF also impaired macrophage phenotype modulation. <i>In vitro</i> experiments revealed that hypoxia alone had minimal direct effects on macrophage polarization but enhanced IL-4-induced M2 polarization, further amplified by SMAD2 and VEGF overexpression. These findings underscore the distinct yet interconnected roles of HIF-1α, SMAD2, and VEGF in shaping the hypoxic renal microenvironment and influencing macrophage polarization. The study highlights VEGF's critical role in renal repair and its interaction with hypoxia and inflammatory pathways, which may modulate macrophage polarization and ultimately impact renal outcomes. These insights suggest a promising therapeutic strategy for kidney diseases.