VEGF ameliorates acute kidney injury by suppressing ferroptosis through activation of the ERK1/2-NRF2 pathway.

Abstract

Vascular endothelial growth factor (VEGF) plays a crucial role in maintaining renal homeostasis. However, the precise impact of VEGF on ferroptosis in acute kidney injury (AKI) remains incompletely understood. This study aims to investigate the effects of VEGF on ferroptosis in the model of AKI and to elucidate the underlying mechanisms. We used C57BL mice and HK-2 cells to construct sepsis-associated AKI models. We assessed renal function, cell viability, and tissue levels of iron, malondialdehyde (MDA), and glutathione (GSH) in mice. Intracellular reactive oxygen species (ROS), mitochondrial membrane potential, and electron microscopy-detected cellular changes were also measured. Western blotting analyzed key ferroptosis-related proteins (SLC7A11, GPX4) and components of the ERK1/2-NRF2-GPX4 pathway. VEGF treatment significantly reduced oxidative stress by lowering ROS and MDA levels while increasing GSH. Additionally, VEGF165 activated the ERK1/2-NRF2 pathway, mitigating ferroptosis.