Renal GSH Content Research Articles

The effects of exogenous glutathione and cysteine on oxidative stress induced by ferric nitrilotriacetate

The effects of the antioxidants, glutathione (GSH) and its precursor cysteine (Cys) on oxidative damage induced by ferric nitrilotriacetate (Fe-NTA) were examined. Fe-NTA-associated oxidative stress caused the depletion of renal cellular GSH content. Administration of exogenous GSH and Cys suppressed 8-hydroxydeoxyguanosine (8-OH-dG) formation, an indicator of oxidative DNA damage and nephrotoxicity following Fe-NTA treatment. This suggests that generation of free radicals may be causally involved in oxidative lesion generation. Since lipid peroxidation was found to be inhibited only by GSH and not Cys treatment, this suggests that this effect and the DNA damage might be mediated by different pathways. Fe-NTA-associated oxidative stress in renal tubular cells might thus operate via both intracellular and external space modes.

Intrinsic susceptibility of the kidney to acetaminophen toxicity in middle-aged rats

Acetaminophen (APAP)-induced nephrotoxicity is age-dependent in male Sprague-Dawley (SD) rats: middle-aged (9–12 months old) rats exhibit nephrotoxicity at lower dosages of APAP than do young adults (2–3 months old). The present study was designed to test the hypothesis that the intrinsic susceptibility of renal tissue to APAP toxicity is increased in middle-aged rats. APAP toxicity was evaluated in renal slices from naive 3- and 12-month-old male SD rats incubated with 0–50 mM APAP for 2–8 h. Renal slice glutathione (GSH) and APAP concentrations were determined; renal function was assessed by organic anion (para-aminohippurate, PAH) and cation (tetraethylammonium, TEA) accumulation; and cell viability was assessed by lactate dehydrogenase (LDH) leakage. At each concentration of APAP tested, accumulation of APAP by renal slices was similar in 3- and 12-month-olds. APAP toxicity in renal slices from both 3- and 12-month-old rats was characterized by concentration-dependent increases in LDH leakage. In contrast to APAP nephrotoxicity in vivo, APAP toxicity in renal slices was accompanied by decreased accumulation of PAH and TEA. Additionally, APAP produced marked reductions in renal slice GSH content in a concentration-dependent manner: however, in contrast to APAP nephrotoxicity in vivo, APAP-induced GSH depletion in vitro did not precede cytotoxicity. No consistent age-dependent differences in the time- and concentration-response curves for APAP nephrotoxicity were observed. These data suggest that APAP cytotoxicity in vitro is not increased in 12-month-old rats. However, since the pattern (and mechanisms) of APAP cytotoxicity in vitro appears to be different from that observed in vivo, extrapolation of in vitro cytotoxicity to in vivo nephrotoxicity is limited. Therefore, age differences in intrinsic susceptibility of the intact kidney cannot be excluded as a mechanism contributing to enhanced APAP nephrotoxicity in middle-aged rats.

Changes in Glutathione Peroxidase System and Pyridine Nucleotide Phosphate Levels in Kidneys of Cephaloridine-Administered Rats

To elucidate the nephrotoxic mechanisms of cephalondine (CER), changes in renal contents of glutathione (GSH), glutathione disulfide (GSSG), reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH and NADP) and changes in renal activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were examined for 15 days in rats that received single intravenous injections of CER in doses of 0 (control), 100 and 1.000 mg/kg body weight. Significantly different changes from the control group were observed in the 1.000 mg/kg group. The 1.000 mg/kg group showed elevations in renal NADP and NADPH contents and decrements in renal GSH content in the period of the 1 st to 3rd hour after the CFR-administration. Thus, the fall in renal GSH content was considered to be a cause for renal injury due to the oxygen radicals observed in the early period. After the 6th hour, the 1.000 mg/kg group showed decreases of renal glutathione peroxidase and glutathione reductase activities and increases of renal glucose-6-phosphate dehydrogenase activity as well as GSH content. Although accumulation of GSH in the kidney was clearly observed in the late period, the more highly aggravated renal injury was speculated to be due to the decreased level in the utilization of GSH according to the fall of renal glutathione peroxidase activity.

Changes in glutathione peroxidase system and pyridine nucleotide phosphate levels in kidneys of cephaloridine-administered rats.

To elucidate the nephrotoxic mechanisms of cephaloridine (CER), changes in renal contents of glutathione (GSH), glutathione disulfide (GSSG), reduced and oxidized nicotinamide adenine dinucleotide phosphates (NADPH and NADP) and changes in renal activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were examined for 15 days in rats that received single intravenous injections of CER in doses of 0 (control), 100 and 1,000 mg/kg body weight. Significantly different changes from the control group were observed in the 1,000 mg/kg group. The 1,000 mg/kg group showed elevations in renal NADP and NADPH contents and decrements in renal GSH content in the period of the 1st to 3rd hour after the CER-administration. Thus, the fall in renal GSH content was considered to be a cause for renal injury due to the oxygen radicals observed in the early period. After the 6th hour, the 1,000 mg/kg group showed decreases of renal glutathione peroxidase and glutathione reductase activities and increases of renal glucose-6-phosphate dehydrogenase activity as well as GSH content. Although accumulation of GSH in the kidney was clearly observed in the late period, the more highly aggravated renal injury was speculated to be due to the decreased level in the utilization of GSH according to the fall of renal glutathione peroxidase activity.

Cyclosporin-mediated increase in kidney glutathione and effects on gamma-glutamyl-cycle enzymes.

The unprecedented ability of cyclosporin A, when given for six days at a dose of 25 mg/kg/d or 50 mg/kg/d, to cause a marked and sustained increase in renal glutathione (GSH) concentration in rat kidney is described. This response was particular to the kidney insofar as the GSH concentration in the liver was not increased in response to a lower dose of cyclosporin and was decreased in the liver of animals treated with the higher dose of the drug. The increase in kidney GSH concentration did not appear to be due to an increased rate of production or to an inhibition of the degradation of the tripeptide. This suggestion is based on the finding that the activities of the GSH synthesis pathways, GSSG-reductase and gamma-glutamylcysteine synthetase, were unchanged or decreased, respectively, and those of the catabolic enzymes, GSH-peroxidase and gamma-glutamyltranspeptidase, were unchanged or increased, respectively. It is suggested that the elevation of renal GSH content in the face of diminished synthetic capacity and an apparent increased utilization may result from an enhanced uptake of GSH as the result of alterations caused by cyclosporin in the renal transport system.