It is well‐known that vascular endothelial growth factor (VEGF) plays a key role in development and pathology, but its function in normal adult tissues is rarely understood. Increased use of anti‐angiogenic therapies targeting VEGF in human pathologies have shown more and more adverse effects. In this report, a conditional expression model (Tet‐On system) was used to down‐regulate podocyte VEGF in adult mice, which resulted in many kidney problems, characterized by glomerular morphological changes, proteinuria, reduced water consumption and urination, increased urine electro‐conductivity, as well as high susceptibility to BSA stress. Our findings indicated that podocyte‐specific VEGF down‐regulation resulted in poor kidney performance and led mice to be more susceptible to further kidney damages. © 2010 IUBMB IUBMB Life, 62(9): 677–683, 2010