Effects of high glucose on cytokine-induced nerve growth factor (NGF) expression in rat renal mesangial cells.

Nerve growth factor (NGF) accumulates at sites of inflammation and modulates local immune reactions. To characterize the mechanisms of cytokine-induced NGF expression under physiological and pathophysiological conditions, we have used cultured glomerular mesangial cells, which play a key role in glomerular inflammatory diseases such as diabetic nephropathy. To study the effects of high glucose on cytokine-induced NGF expression, rat mesangial cells were treated with the cytokines interleukin-1beta and tumor necrosis factor alpha under normal (1.0 g/L) and high (4.5 g/L) glucose concentrations. In the presence of high glucose concentrations, the cytokines drastically potentiated NGF protein but not mRNA expression when compared to physiological glucose levels. The specific protein kinase C inhibitors Ro31-8220 and CGP41251 suppressed cytokine-induced NGF expression. Moreover, blocking the oxidative activation of the protein kinase C pathway by N-acetylcysteine inhibited glucose effects on NGF synthesis. Neutralizing antibodies against transforming growth factor-beta inhibited cytokine-induced NGF expression under normal glucose concentrations but not under high glucose conditions. Enhanced expression of NGF under high glucose conditions may contribute to kidney diseases such as diabetic nephropathy.