Oxidative stress in the pathogenesis of experimental mesangial proliferative glomerulonephritis. Am J Physiol Renal Physiol 2003 Dec;285(6):F1138-48
Date
11/06/2003Pubmed ID
14600028DOI
10.1152/ajprenal.00397.2002Scopus ID
2-s2.0-0242581714 (requires institutional sign-in at Scopus site) 54 CitationsAbstract
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.
Author List
Budisavljevic MN, Hodge L, Barber K, Fulmer JR, Durazo-Arvizu RA, Self SE, Kuhlmann M, Raymond JR, Greene ELAuthor
John R. Raymond MD President, CEO, Professor in the President department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntioxidants
Cell Division
Cells, Cultured
Glomerular Mesangium
Glomerulonephritis, Membranoproliferative
Growth Substances
Isoantibodies
Male
Mitogen-Activated Protein Kinases
Oxidative Stress
Phosphorylation
RNA, Messenger
Rats
Rats, Wistar
Thioctic Acid
Transcription, Genetic
Transforming Growth Factor beta
Transforming Growth Factor beta1
