F2-isoprostanes mediate high glucose-induced TGF-β synthesis and glomerular proteinuria in experimental type I diabetes
F2-isoprostanes mediate high glucose-induced TGF-β synthesis and glomerular proteinuria in experimental type I diabetes
复制标题
DOI：
10.1046/j.1523-1755.2000.00368.x
复制
发表时间：
2000-11-01
影响因子：
19.6
通讯作者：
Badr, KF
中科院分区：
文献类型：
--
作者：
Montero, A;Munger, KA;Badr, KF
背景。最近发现的花生四烯酸衍生物异前列腺素在与氧化应激相关的病理条件下增加，如糖尿病。在糖尿病肾病的发展过程中，尚未描述异前列腺素的作用。高葡萄糖环境下的细胞培养已被用作阐明糖尿病肾病的细胞机制的模型。在参与高糖作用的生长因子中，转化生长因子- β (tgf - β)已被描述为在肾病的发展中起关键作用。在链脲佐菌素诱导的糖尿病大鼠日粮中添加抗氧化维生素E （1000 U/kg日粮）。取血样和尿样测定肾功能和异前列腺素浓度，用气相色谱/质谱法测定。在高糖环境下培养肾小球系膜细胞和内皮细胞，观察异前列腺素的合成以及异前列腺素在高糖诱导的tgf - β合成中的作用。链脲佐菌素诱导的糖尿病大鼠血浆中f -2异前列腺素水平和尿排泄率明显升高。膳食补充维生素E使（血浆）异前列腺素水平正常化并降低（尿）异前列腺素水平，令人惊讶的是，改善了蛋白尿和血尿素氮（BUN）水平。高环境葡萄糖增加了培养的肾小球内皮细胞和系膜细胞中f -2异前列腺素的合成。用f -2异前列腺素孵育肾小球细胞可刺激tgf - β的产生。糖尿病期间f -2-异前列腺素合成的增加似乎是肾脏tgf - β增加的部分原因，tgf - β是糖尿病肾病的一种众所周知的介质。
Background. The recently discovered arachidonic acid derivatives, isoprostanes, are increased in pathological conditions associated with oxidative stress, such as diabetes. No role has yet been described for isoprostanes during the development of diabetic nephropathy. Cell culture in high ambient glucose has been used as a model in elucidating cellular mechanisms underlying diabetic nephropathy. Among the growth factors involved in the effect of high glucose, transforming growth factor-beta (TGF-beta) has been described as playing a key role in the development of nephropathy.Methods. Streptozotocin-induced diabetic rats were supplemented in their diet with the antioxidant vitamin E (1000 U/kg diet). Blood and urine samples were taken to determine renal function and isoprostane concentration, as determined by gas chromatography/mass spectrometry. Glomerular mesangial and endothelial cells were cultured in high ambient glucose to determine the synthesis of isoprostanes and the role of isoprostanes in high glucose-induced synthesis of TGF-beta.Results. Streptozotocin-induced diabetic rats had marked increases in plasma levels and urinary excretion rates of F-2-isoprostanes. Dietary supplementation with vitamin E normalized (plasma) and reduced (urine) isoprostane levels and, surprisingly, improved proteinuria and blood urea nitrogen (BUN) levels. High ambient glucose increased F-2-isoprostane synthesis in glomerular endothelial and mesangial cells in culture. Incubation of glomerular cells with F-2-isoprostanes stimulated the production of TGF-beta.Conclusions. Increased F-2-isoprostane synthesis during diabetes appears to be responsible in part for the increase in renal TGF-beta, a well-known mediator of diabetic nephropathy.