Previously, we demonstrated that upstream stimulatory factor 2 (USF2) transgenic mice (USF2 (Tg) mice) developed nephropathy including albuminuria and glomerular hypertrophy, accompanied by increased TGF- and fibronectin accumulation in the glomeruli. However, the mechanisms by which overexpression of USF2 induces kidney injury are unknown. USF has been shown to regulate renin expression. Moreover, the renin-angiotensin system (RAS) plays important roles in renal diseases. Therefore, in the current studies, the effects of USF2 on the regulation of RAS in the kidney as well as in mesangial cells from USF2 transgenic mice were examined. The role of USF2-mediated regulation of RAS in TGF- production in mesangial cells was also determined. Our data demonstrate that USF2 (Tg) mice exhibit increased renin and angiotensin II (AngII) levels in the kidney. In contrast, renal expression of other components of RAS such as renin receptor, angiotensinogen, ACE, ACE2, AT1a receptor, and AT2 receptor were not altered in USF2 (Tg) mice. Similarly, mesangial cells isolated from USF2 (Tg) mice had increased renin and AngII levels. Mesangial cells over-expressing USF2 also had increased TGF- production, which was blocked by siRNA-mediated renin gene knock down or RAS blockade (enalapril or losartan). Collectively, these results suggest that USF2 promotes renal renin expression and stimulates AngII generation, leading to activation of the intrarenal RAS. In addition, renin-dependent AngII generation mediates the effect of USF2 on TGF- production in mesangial cells, which may contribute to the development of nephropathy in USF2 (Tg) mice.