Diabetic nephropathy is the most common cause of end-stage renal failure in the United States. Hyperglycemia is an important factor in the pathogenesis of diabetic nephropathy. Hyperglycemia up-regulates the expression of transforming growth factor- (TGF-), which stimulates extracellular matrix deposition in the kidney, contributing to the development of diabetic nephropathy. Our previous studies demonstrated that the transcription factor, Upstream Stimulatory Factor 2 (USF2), was up-regulated by high glucose, which bound to an 18 bp sequence in the thrombospondin1 (TSP1) gene promoter and regulated high glucose-induced TSP1 expression and TGF- activity in mesangial cells, suggesting that USF2 might play a role in the development of diabetic nephropathy. In the present studies, we examined the effect of over-expression of USF2 on the development of diabetic nephropathy. Type 1 diabetes was induced in USF2 transgenic mice (USF2 (Tg)) and their wild type littermates (WT) by injection of streptozotocin. Four groups of mice were studied: control WT, control USF2 (Tg), diabetic WT, and diabetic USF2 (Tg). Mice were sacrificed after 15 weeks of diabetes onset. At the end of studies, control USF2 (Tg) mice (about 6 month old) exhibited increased urinary albumin excretion. These mice also exhibited glomerular hypertrophy, accompanied by increased TSP1, active TGF-, fibronectin accumulation in the glomeruli compared with control wild type littermates. Type 1 diabetes onset further augmented the urinary albumin excretion and glomerular hypertrophy in the USF2 (Tg) mice. These findings suggest that over-expression of USF2 accelerates the development of diabetic nephropathy.