Oxidative stress in the pathogenesis of experimental mesangial proliferative glomerulonephritis.
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-beta1 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.
Budisavljevic
Milos N
MN
Nephrology Division, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425, USA. budisamn@musc.edu
Hodge
LeAnn
L
Barber
Kelli
K
Fulmer
John R
JR
Durazo-Arvizu
Ramon A
RA
Self
Sally E
SE
Kuhlmann
Martin
M
Raymond
John R
JR
Greene
Eddie L
EL
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D015432:Glomerulonephritis, Membranoproliferative / Q000378:metabolism* / Q000473:pathology*; D006133:Growth Substances / Q000494:pharmacology; D007518:Isoantibodies / Q000494:pharmacology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D008063:Thioctic Acid / Q000494:pharmacology; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D000975:Antioxidants; D006133:Growth Substances; D007518:Isoantibodies; D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C035678:anti-Thy antibody; D008063:Thioctic Acid; D020928:Mitogen-Activated Protein Kinases