A. Ceriello et al., Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy, DIABETES, 49(12), 2000, pp. 2170-2177
There is an individual susceptibility to diabetic nephropathy, and oxidativ
e stress is believed to play an important role in the pathogenesis of diabe
tic complications. Active oxygen species induce antioxidant enzyme expressi
on in tissues, an effect considered to be a defensive mechanism. To test wh
ether altered intracellular antioxidant enzyme production might explain the
predisposition to diabetic nephropathy, we studied the effect of long-term
(12 weeks) exposure to normal (5 mmol/l) or high (22 mmol/l) glucose conce
ntrations on fibroblast antioxidant enzyme gene expression and protein acti
vity in type 1 diabetic patients with and without nephropathy, nondiabetic
nephropathic patients, and nondiabetic control subjects. Under conditions o
f normal glucose concentration in the culture media, CuZnSuperoxide-dismuta
se, MnSnperoxide-dismutase, catalase, and glutathione-peroxidase activity a
nd mRNA expression were not different among the four groups. Under high-glu
cose conditions, CnZnSu-peroxide-dismutase mRNA and activity increased simi
larly in all groups (P < 0.001 vs. basal), whereas MnSu-peroxide-dismutase
did not change. In contrast, catalase mRNA and activity as well as glutathi
one-peroxidase mRNA and activity increased in fibroblasts from type 1 diabe
tic patients without nephropathy (P < 0.001), in fibroblasts from nondiabet
ic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic c
ontrol subjects (P < 0.001), but not in fibroblasts from type 1 diabetic pa
tients with nephropathy. Exposure to high glucose concentrations significan
tly increased Lipid peroxidation in cells, higher levels being found in cel
ls from diabetic patients with nephropathy (P < 0.001). These data, while c
onfirming that exposure to high glucose concentrations induces an antioxida
nt defense in skin fibroblasts from normal subjects, demonstrate a failure
of this defensive mechanism in cells from type 1 diabetic patients with nep
hropathy, whereas skin fibroblasts from diabetic patients without complicat
ions or from nondiabetic nephropathic patients have an intact antioxidant r
esponse to glucose-induced oxidative stress.