Abstract

Podocyte injury is the major cause of proteinuria in primary glomerular diseases. Oxidative stress has long been thought to play a role in triggering podocyte damage; however, the underlying mechanism remains poorly understood. Here we show that the Wnt/β-catenin pathway is involved in mediating oxidative stress-induced podocyte dysfunction. Advanced oxidation protein products, a marker and trigger of oxidative stress, were increased in the serum of patients with chronic kidney disease and correlated with impaired glomerular filtration, proteinuria, and circulating level of Wnt1. Both serum from patients with chronic kidney disease and exogenous advanced oxidation protein products induced Wnt1 and Wnt7a expression, activated β-catenin, and reduced expression of podocyte-specific markers in vitro and in vivo . Blockade of Wnt signaling by Klotho or knockdown of β-catenin by shRNA in podocytes abolished β-catenin activation and the upregulation of fibronectin, desmin, matrix metalloproteinase-9, and Snail1 triggered by advanced oxidation protein products. Furthermore, conditional knockout mice with podocyte-specific ablation of β-catenin were protected against podocyte injury and albuminuria after treatment with advanced oxidation protein products. The action of Wnt/β-catenin was dependent on the receptor of advanced glycation end products (RAGE)–mediated NADPH oxidase induction, reactive oxygen species generation, and nuclear factor-κB activation. These studies uncover a novel mechanistic linkage of oxidative stress, Wnt/β-catenin activation, and podocyte dysfunction.