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Identification of copper/zinc superoxide dismutase as a novel nitric oxide‐regulated gene in rat glomerular mesangial cells and kidneys of endotoxemic rats
Author(s) -
Frank Stefan,
Zacharowski Kai,
Wray Gillian M.,
Thiemermann Christoph,
Pfeilschifter Josef
Publication year - 1999
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.13.8.869
Subject(s) - peroxynitrite , superoxide dismutase , nitric oxide , chemistry , in vivo , lipopolysaccharide , nitric oxide synthase , dismutase , pharmacology , inflammation , gene expression , biochemistry , medicine , endocrinology , microbiology and biotechnology , superoxide , enzyme , biology , gene , organic chemistry
To define the mechanism of nitric oxide (NO) action in the glomerulus, we attempted to identify genes that are regulated by NO in rat glomerular mesangial cells. We identified a Cu/Zn superoxide dismutase (SOD) that was strongly induced in these cells by treatment with S‐nitrosoglutathione as a NO‐donating agent. Bacterial lipopolysaccharide (LPS) acutely decreased Cu/Zn SOD mRNA levels. The LPS‐mediated decrease in Cu/Zn SOD is reversed by endogenously produced NO, as LPS also induced a delayed strong iNOS expression in these cells in vitro , which is accompanied by increased Cu/Zn SOD expression. NO dependency of Cu/Zn SOD mRNA recovery could be demonstrated by inhibition of this process by L‐N G ‐monomethylarginine, an inhibitor of NOS enzymatic activity. To demonstrate the in vivo relevance of our observations, we have chosen LPS‐treated rats as a model for induction of a systemic inflammatory response. In these animals, we demonstrate a direct coupling of Cu/Zn SOD expression levels to the presence of NO, as Cu/Zn SOD mRNA levels declined during acute inflammation in the presence of a selective inhibitor of iNOS. We propose that the up‐regulation of Cu/Zn SOD by endogenous NO may serve as an adaptive, protective mechanism to prevent the formation of toxic quantities of peroxynitrite in conditions associated with iNOS induction during endotoxic shock.—Frank, S., Zacharowski, K., Wray, G. M., Thiemermann, C., Pfeilschifter, J. Identification of copper/zinc superoxide dismutase as a novel nitric oxide‐regulated gene in rat glomerular mesangial cells and kidneys of endotoxemic rats. FASEB J. 13, 869–882 (1999)