The accumulation of plasma advanced oxidation protein products (AOPPs) is prevalent in diverse disorders such as diabetes, metabolic syndromes, and chronic kidney disease. To study whether accumulated AOPPs have an important role in the progression of proteinuria and glomerulosclerosis, we chronically treated normal Sprague-Dawley rats with AOPP-modified rat serum albumin. Podocyte apoptosis was significantly increased coincident with the onset of albuminuria and preceded significant losses of glomerular podocytes. Increasing the amount of AOPPs in the media of conditionally immortalized podocytes rapidly triggered the production of intracellular superoxide by activation of NADPH oxidase and this, in turn, led to an upregulation of p53, Bax, caspase 3 activity, and apoptosis. Chronic inhibition of NADPH oxidase by apocynin prevented podocyte apoptosis, ameliorated podocyte depletion, and decreased albuminuria in AOPP-challenged rats. Our study demonstrates that accumulation of AOPPs promotes NADPH oxidase-dependent podocyte depletion by a p53-Bax apoptotic pathway both in vivo and in vitro.