Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. The basic defect lies within the IgA immune system and in peripheral blood leukocytes, rather than local kidney abnormalities. To define the intracellular mechanisms leading to the disease, we conducted a microarray study to identify genes and pathways differentially modulated in peripheral blood leukocytes isolated from 12 IgAN patients and 8 healthy controls. The genes whose expression discriminated between the IgAN patients and controls were primarily involved in canonical WNT-Β-catenin and PI3K/Akt pathways. We also tested peripheral blood mononuclear cells and their subpopulations isolated from an independent group of IgAN patients and healthy controls. There were low protein levels of inversin and PTEN, key regulators of WNT-Β-catenin and PI3K/Akt, in IgAN patients, suggesting hyperactivation of these pathways. Also, there were increased phospho-Akt protein levels and nuclear Β-catenin accumulation with an enhanced peripheral blood mononuclear cell proliferation rate. Subpopulation analysis uncovered a major irregularity of WNT signaling in monocytes. Hence, hyperactivation of these pathways may provide insight into mechanisms contributing to the pathogenesis of IgAN. © 2010 International Society of Nephrology.