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Am J Physiol Renal Physiol 285: F1138-F1148, 2003; doi:10.1152/ajprenal.00397.2002
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Oxidative stress in the pathogenesis of experimental mesangial proliferative glomerulonephritis

Milos N. Budisavljevic,1,2 LeAnn Hodge,1 Kelli Barber,1 John R. Fulmer,1 Ramon A. Durazo-Arvizu,3 Sally E. Self,4 Martin Kuhlmann,5 John R. Raymond,1,2 and Eddie L. Greene6

1Division of Nephrology, 3Department of Biometry, and 4Department of Pathology and Laboratory Medicine, Medical University of South Carolina, and 2Medical and Research Services, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29425; 5Department of Internal Medicine, Universitatskliniken des Saarlandes, 66421 Homburg/Saar, Germany; and 6Division of Nephrology, Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905

Submitted 7 November 2002 ; accepted in final form 11 August 2003

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 {alpha}-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 {alpha}-lipoic acid. Treatment with {alpha}-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-{beta}1 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 {alpha}-lipoic acid. The effects of {alpha}-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 {alpha}-lipoic acid. We suggest that ROS may mediate glomerular injury by inducing ERK phosphorylation. {alpha}-Lipoic acid should be considered a potential therapeutic agent in certain types of human GN.

{alpha}-lipoic acid; anti-Thy 1 nephritis; extracellular signal-regulated kinase; {alpha}-smooth muscle actin; transforming growth factor-{beta}1


Address for reprint requests and other correspondence: M. N. Budisavljevic, Nephrology Div., Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425 (E-mail: budisamn{at}musc.edu).




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