N-acetyl cysteine blocks mesangial VCAM-1 and NF-kappa B expression in vivo.
Inducible vascular cell adhesion molecule-1 (VCAM-1) in glomerular mesangial cells (GMC) exposed to lipopolysaccharide (LPS) in vitro involves the activation of nuclear factor-kappa B (NF-kappa B) and its interaction with the proximal VCAM-1 promoter. We used a murine model to assess the effect of the antioxidant, N-acetyl cysteine on GMC activation in vivo. Single intraperitoneal administration of N-acetyl cysteine completely suppressed LPS-induced VCAM-1 expression on the GMC surface. When an oligonucleotide spanning the NF-kappa B binding region of the VCAM-1 promoter was incubated with extracts from the renal cortex of LPS-treated animals, a single nucleoprotein complex formed. This complex was composed of p50 and p65, but not p52, c-Rel, or RelB, and its formation was dramatically inhibited by pretreatment with N-acetyl cysteine, D,L-Buthionine-[S,R]-sulfoximide, a compound that depletes glutathione, augmented VCAM-1 expression inducible with a suboptimal amount of LPS to levels comparable with using 50 micrograms of LPS alone, D,L-Buthionine-[S,R]-sulfoximide also potentiated the p50-p65 binding activity induced with a suboptimal amount of LPS. These data provide a redox-sensitive, transcriptional link between NF-kappa B and VCAM-1 in GMC in vivo and implicate oxidative stress as an important regulatory signal in the pathogenesis of glomerular mesangial cell disorders.
Khachigian
L M
LM
Centre for Thrombosis and Vascular Research, School of Pathology, University of New South Wales, Sydney, Australia.
Collins
T
T
Fries
J W
JW
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*
D000963:Antimetabolites; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D019328:Buthionine Sulfoximine; D000111:Acetylcysteine