Calcineurin (CaN) is activated in diabetes and plays a role in glomerular hypertrophy and extracellular matrix (ECM) accumulation. Here, kidneys from diabetic model mice were investigated for the expression of the regulator of CaN 1 (RCAN1) isoform 4 (RCAN1. 4) which had been shown to be transcriptionally upregulated by CaN activation. We found the increased immunoreactivity for RCAN1 in the glomerular cells of db/db mice and streptozotocin-induced diabetic mice. In concordance, the expression of RCAN1 protein and RCAN1. 4 mRNA were elevated in the whole kidney sample from db/db mice. Interleukin-1β (IL-1β), tumor necrosis factor-α, and glycated albumin (AGE-BSA) were identified as inducers of RCAN1. 4 in mesangial cells. Pretreatment of cyclosporine A blocked the increases of RCAN1. 4 stimulated by IL-1β or AGE-BSA, suggesting that activation of CaN is required for the RCAN1. 4 induction. Stable transfection of RCAN1. 4 in Mes-13 mesangial cells upregulated several factors relevant to ECM production and degradation. These results suggested that RCAN1. 4 might act as a link between CaN activation and ECM turnover in diabetic nephropathy.