Enhanced gamma-glutamyl transpeptidase expression and superoxide production in Mpv17(-/-) glomerulosclerosis mice

Recently, gamma -glutamyl transpeptidase, which initiates cleavage of extra cellular glutathione, has been shown to promote oxidative damage to cells. Here we examined a murine disease model of glomerulosclerosis, involving lo ss of the Mpv17 gene coding for a peroxisomal protein. In Mpv17(-/-) cells, enzyme activity and mRNA expression (examined by quantitative RT-PCR) of m embrane-bound gamma -glutamyl transpeptidase were increased, while plasma g lutathione peroxidase and superoxide dismutase levels were lowered. Superox ide anion production in these cells was increased as documented by electron spin resonance spectroscopy. In the presence of Mn(III)tetrakis(4-benzoic acid)porphyrin, the activities of gamma -glutamyl transpeptidase and plasma glutathione peroxidase were unchanged, suggesting a relationship between e nzyme expression and the amount of reactive oxygen species. Inhibition of g amma -glutamyl transpeptidase by acivicin reverted the lowered plasma gluta thione peroxidase and superoxide dismutase activities, indicating reciproca l control of gene expression for these enzymes.