Chronic elevated glucose levels and activation of the renal renin-angiotensin system have been implicated in the pathogenesis of diabetic nephropathy (DN). We tested the ability of lisofylline (LSF), a novel anti-inflammatory compound, to prevent extracellular matrix (ECM) accumulation and growth factor production by human mesangial cells (HMC) cultured in chronic elevated glucose (HG) or Angiotensin II (AngII). HMC were cultured in normal glucose (NG) (5.5 mM) and in HG (25 mM) for 7d or with 10^-7 AngII for 4 h +/- LSF. Levels of the ECM protein fibronectin and TGF- in media were shown to increase in HG compared with NG. LSF decreased HG-induced fibronectin and TGF production to control levels. Increased expression of collagen type IV and laminin was observed in AngII cultured HMC. LSF protected HMC from the AngII- induction of these key matrix proteins. cAMP-responsive binding-element (CREB) phosphorylation was significantly higher in both HG and AngII cultured HMC. LSF reduced phosphorylation of both CREB and p38 MAPK to control. These data demonstrate that LSF protects HMC from HG- and AngII-mediated ECM deposition by the reduction of matrix protein secretion possibly through regulation of TGF production and modulation of the p38 MAPK pathway. These results suggest that LSF may provide therapeutic benefit for prevention or treatment of DN.