Reactive oxygen species (ROS) are increasingly believed to be important intracellular signaling molecules in mitogenic pathways involved in the pathogenesis of glomerulonephritis (GN). We explored the effects of the antioxidants α-lipoic acid and N-acetyl-L-cysteine on ERK activation in cultured mesangial cells and the role of ERK activation in the severity of glomerular injury in a rat model of anti-Thy 1 GN. In cultured mesangial cells, growth factors stimulated ERK phosphorylation by 150-450%. Antioxidants reduced this increase by 50-60%. Induction of anti-Thy 1 nephritis in rats led to a 210% increase in glomerular ERK phosphorylation. This increase in phosphorylated ERK was reduced by 50% in animals treated with α-lipoic acid. Treatment with α-lipoic acid resulted in significant improvement of glomerular injury. Cellular proliferation was reduced by 100%, and the number of proliferating cell nuclear antigen-positive cells was reduced by 64%. The increased expression of glomerular transforming growth factor-β1 protein and mRNA in rats with anti-Thy 1 nephritis was significantly attenuated and mesangial cell transformation into myofibroblasts was completely prevented by treatment with α-lipoic acid. The effects of α-lipoic acid were at least partially due to inhibition of oxidative stress. In rats with anti-Thy 1 nephritis, ROS production was increased 400-500%, and this increase was inhibited by 55% by treatment with α-lipoic acid. We suggest that ROS may mediate glomerular injury by inducing ERK phosphorylation α-Lipoic acid should be considered a potential therapeutic agent in certain types of human GN.
- Anti-Thy 1 nephritis
- Extracellular signal-regulated kinase
- Transforming growth factor-β1
- α-lipoic acid
- α-smooth muscle actin
ASJC Scopus subject areas