Background Previously, by using proteomic analysis and RNA-seq in isolated glomeruli, we identified several novel differentially expressed proteins in human and mouse diabetic nephropathy (DN) vs control, including DAAM2. DAAM2, the disheveled associated activator of morphogenesis 2 protein, binds the Wnt effector Disheveled. We now aimed to study possible contributions of DAAM2 to DN. Methods We assessed DAAM2 by immunostaining in non-cancer regions of human nephrectomy (Nx), DN and normal donor kidney tissues. We also examined DAAM2 in DN mice (db/db/eNOS-/-) and Nx mice. DN mice treated with angiotensin converting enzyme inhibitor (ACEI) or dipeptidyl peptidase 4 inhibitor (DPP4I) or vehicle were compared. DAAM2 was knocked down in primary cultured podocytes by siRNA to study its effects on cell function. Results In normal human glomeruli, DAAM2 was expressed only on podocytes. DAAM2 expression was increased in both Nx and DN vs normal donors. Podocyte DAAM2 expression was increased in DN and Nx mouse models. Glomerular DAAM2 expression correlated with glomerular size and was decreased significantly by ACEI, while DPP4I only numerically reduced DAAM2. In primary cultured podocytes, knock down of DAAM2 enhanced adhesion, slowed migration, activated Wnt/β-catenin signaling and downregulated mTORC1 and Rho activity. Conclusions Podocyte DAAM2 is upregulated in both nephrectomy and DN, which could be contributed to by glomerular hypertrophy. We hypothesize that DAAM2 regulates podocyte function through the mTORC1, Wnt/β-catenin and Rho signaling pathways.