Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy
Defective intracellular antioxidant enzyme production in type 1 diabetic patients with nephropathy
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DOI：
10.2337/diabetes.49.12.2170
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发表时间：
2000-12-01
期刊：
影响因子：
7.7
通讯作者：
Viberti, GC
中科院分区：
文献类型：
--
作者：
Ceriello, A;Morocutti, A;Viberti, GC
糖尿病肾病有个体易感性，氧化应激被认为在糖尿病并发症的发病机制中起重要作用。活性氧能诱导组织中抗氧化物酶的表达，这种作用被认为是一种防御机制。为了验证细胞内抗氧化酶产生的改变是否可以解释糖尿病肾病的易感性，我们研究了长期(12周)暴露于正常浓度(5 mmoL/L)和高浓度(22 mmoL/L)葡萄糖对1型糖尿病伴和不伴肾病患者、非糖尿病肾病患者和非糖尿病对照组成纤维细胞抗氧化酶基因表达和蛋白活性的影响。在培养液中葡萄糖浓度正常的情况下，4组细胞的铜锌超氧化物歧化酶、锰锡过氧化物酶、过氧化氢酶、谷胱甘肽过氧化物酶活性及基因表达水平无明显差异。在高糖条件下，各组CnZSU-过氧化物酶的表达和活性均有类似的升高(P<；0.001与基础值相比)，而MNSU-过氧化物酶活性无明显变化。相反，在无肾病的1型糖尿病患者(P<；0.001)、非糖尿病肾病患者(P<；0.001)和非糖尿病对照组(P<；0.001)的成纤维细胞中，过氧化氢酶基因和活性以及谷胱甘肽过氧化物酶的基因和活性增加，而在有肾脏病变的1型糖尿病患者的成纤维细胞中则不增加。暴露在高糖浓度下显著增加了细胞中的脂质过氧化，糖尿病肾病患者的细胞中发现了更高的水平(P<；0.001)。这些数据证实，暴露在高糖浓度下会诱导正常人皮肤成纤维细胞的抗氧化防御，但在有肾病的1型糖尿病患者的细胞中，这种防御机制是失败的，而来自没有并发症的糖尿病患者或非糖尿病肾病患者的皮肤成纤维细胞对葡萄糖诱导的氧化应激具有完整的抗氧化反应。
There is an individual susceptibility to diabetic nephropathy, and oxidative stress is believed to play an important role in the pathogenesis of diabetic complications. Active oxygen species induce antioxidant enzyme expression in tissues, an effect considered to be a defensive mechanism. To test whether 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 concentrations on fibroblast antioxidant enzyme gene expression and protein activity in type 1 diabetic patients with and without nephropathy, nondiabetic nephropathic patients, and nondiabetic control subjects. Under conditions of normal glucose concentration in the culture media, CuZnSuperoxide-dismutase, MnSnperoxide-dismutase, catalase, and glutathione-peroxidase activity and mRNA expression were not different among the four groups. Under high-glucose conditions, CnZnSu-peroxide-dismutase mRNA and activity increased similarly in all groups (P < 0.001 vs. basal), whereas MnSu-peroxide-dismutase did not change. In contrast, catalase mRNA and activity as well as glutathione-peroxidase mRNA and activity increased in fibroblasts from type 1 diabetic patients without nephropathy (P < 0.001), in fibroblasts from nondiabetic nephropathic patients (P < 0.001), and in fibroblasts from nondiabetic control subjects (P < 0.001), but not in fibroblasts from type 1 diabetic patients with nephropathy. Exposure to high glucose concentrations significantly increased Lipid peroxidation in cells, higher levels being found in cells from diabetic patients with nephropathy (P < 0.001). These data, while confirming that exposure to high glucose concentrations induces an antioxidant defense in skin fibroblasts from normal subjects, demonstrate a failure of this defensive mechanism in cells from type 1 diabetic patients with nephropathy, whereas skin fibroblasts from diabetic patients without complications or from nondiabetic nephropathic patients have an intact antioxidant response to glucose-induced oxidative stress.