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Enhanced gamma-glutamyl transpeptidase expression and superoxide production in Mpv17-/- glomerulosclerosis mice
G Wagner1, K Stettmaier, W Bors
1Institut für Physiologische Chemie I, Heinrich-Heine-Universität, Düsseldorf, Germany.
Abstract:
Recently, gamma-glutamyl transpeptidase, which initiates cleavage of extracellular glutathione, has been shown to promote oxidative damage to cells. Here we examined a murine disease model of glomerulosclerosis, involving loss of the Mpv17 gene coding for a peroxisomal protein. In Mpv17-/- cells, enzyme activity and mRNA expression (examined by quantitative RT-PCR) of membrane-bound gamma-glutamyl transpeptidase were increased, while plasma glutathione peroxidase and superoxide dismutase levels were lowered. Superoxide 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 enzyme expression and the amount of reactive oxygen species. Inhibition of gamma-glutamyl transpeptidase by acivicin reverted the lowered plasma glutathione peroxidase and superoxide dismutase activities, indicating reciprocal control of gene expression for these enzymes.
Insights
Gamma-glutamyl transpeptidase promotes oxidative damage. Inhibiting this enzyme in a mouse model of glomerulosclerosis restored antioxidant enzyme levels, suggesting a therapeutic target.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Background:
- Gamma-glutamyl transpeptidase (GGT) initiates extracellular glutathione cleavage, contributing to cellular oxidative damage.
- Glomerulosclerosis is a kidney disease characterized by glomeruli damage.
- The Mpv17 gene codes for a peroxisomal protein crucial for kidney function.
Purpose of the Study:
- To investigate the role of gamma-glutamyl transpeptidase in a murine model of glomerulosclerosis.
- To explore the relationship between Mpv17 gene loss, GGT activity, and oxidative stress.
- To assess the potential of GGT inhibition as a therapeutic strategy.
Main Methods:
- Utilized a murine model with Mpv17 gene knockout (Mpv17-/-).
- Quantified membrane-bound GGT activity and mRNA expression using quantitative RT-PCR.
- Measured plasma levels of glutathione peroxidase (GPx) and superoxide dismutase (SOD).
- Assessed superoxide anion production via electron spin resonance (ESR) spectroscopy.
- Investigated the effects of Mn(III)tetrakis(4-benzoic acid)porphyrin and acivicin (GGT inhibitor).
Main Results:
- Mpv17-/- cells exhibited increased GGT activity and mRNA expression.
- Lowered plasma GPx and SOD levels were observed in Mpv17-/- mice.
- Elevated superoxide anion production was detected in Mpv17-/- cells.
- GGT inhibition by acivicin normalized plasma GPx and SOD activities.
- Mn(III)tetrakis(4-benzoic acid)porphyrin did not alter GGT or GPx activities.
Conclusions:
- Loss of the Mpv17 gene exacerbates oxidative stress in glomerulosclerosis.
- Increased GGT activity is linked to elevated reactive oxygen species production.
- Inhibiting GGT can restore antioxidant enzyme levels, suggesting a reciprocal regulatory mechanism.
- GGT inhibition presents a potential therapeutic avenue for glomerulosclerosis and associated oxidative damage.
