High fructose diet has been proposed as a major contributor to metabolic syndrome, which is usually accompanied with proteinuria due to glomerular podocyte injury. However, the underlying pathological mechanisms of fructose-induced podocyte injury remain elusive. In this study, we have used an iTRAQ based quantitative proteomic strategy to comprehensively characterize the dynamic proteome changes in glomeruli of high fructose-fed rats, and revealed global fructose-induced glomerular metabolic reprogramming at four different stages during the progression of high fructose modeling.