Selenium-deficient diet induces renal oxidative stress and injury via TGF-β1 in normal and diabetic rats
Selenium-deficient diet induces renal oxidative stress and injury via TGF-β1 in normal and diabetic rats
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DOI：
10.1046/j.1523-1755.2001.0590041342.x
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发表时间：
2001-04-01
影响因子：
19.6
通讯作者：
Bollineni, JS
中科院分区：
文献类型：
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作者：
Reddi, AS;Bollineni, JS
背景氧化应激与糖尿病肾病的发病机制有关。虽然葡萄糖本身可以引发氧化应激，但必需微量元素如硒（Se）的缺乏加剧了糖尿病大鼠的氧化应激。硒缺乏引起氧化应激和肾损伤的机制尚不完全清楚。本研究验证了硒缺乏通过转化生长因子-β 1（TGF-β 1）诱导肾氧化应激和肾损伤的假说。使用了54只雄性Wistar大鼠。27只大鼠用链脲佐菌素诱发糖尿病，另27只大鼠只接受缓冲液。诱导糖尿病10周后，处死正常和糖尿病大鼠，取出肾脏，分离肾小球。将正常和糖尿病大鼠的肾小球在单独的TCF-β 1或其中和抗体存在下孵育。测定抗氧化酶（Cu-Zn）、超氧化物歧化酶（Cu-Zn SOD）、过氧化氢酶和谷胱甘肽过氧化物酶（GSH-Px）活性;总谷胱甘肽;和脂质过氧化作用。在硒研究中，15只正常大鼠和15只糖尿病大鼠被分为5组，每组5只，在诱导糖尿病后一周喂以常规、缺硒或补硒的饮食。喂食这些饲料10周后，处死大鼠并分离gromeruli。通过测定抗氧化酶和TGF-β 1的mRNA表达来检查氧化应激。测定血糖和尿蛋白。光镜下观察肾脏和小叶间动脉的组织学变化。体外研究表明，TGF-β 1显着降低肾小球过氧化氢酶和GSH-Px的活动，以及总谷胱甘肽水平与脂质过氧化作用的增加，在正常和糖尿病大鼠。TGF-β抗体消除了这些变化。TGF-β 1对Cu-Zn SOD无影响。与TGF-β 1一样，缺硒饮食导致肾小球Cu-Zn SOD、过氧化氢酶和GSH-Px mRNA表达显著降低，但TGF-β 1 mRNA表达显著增加。此外，硒缺乏的饮食引起蛋白尿，肾小球硬化，血糖水平在正常和糖尿病大鼠的增加。饮食不足导致小叶间动脉管腔缩小。糖尿病大鼠补硒上调抗氧化酶的mRNA表达，并显着降低，但没有正常化的TGF-β 1。补硒可使糖尿病大鼠肾小球硬化恢复正常，小叶间动脉管腔明显扩大。同时，补硒对糖尿病大鼠肾小管上皮细胞有保护作用。数据显示，TGF-β 1是一种促氧化剂，硒缺乏通过这种生长因子增加氧化应激。此外，硒缺乏可模拟高血糖状况。糖尿病大鼠补充硒不仅可以预防氧化应激，还可以预防肾脏结构损伤。
Background. Oxidative stress has been implicated in the pathogenesis of diabetic nephropathy. Although glucose itself can initiate oxidative stress, deficiency of essential trace elements such as selenium (Se) map exacerbate this oxidative stress in diabetic rats. The mechanism by which Se deficiency causes oxidative stress and renal injury is not completely understood. This study tested the hypothesis that Se deficiency induces renal oxidative stress and renal injury via transforming growth factor-beta1 (TGF-beta1).Methods. Fifty-four male Wistar rats were used. Diabetes was induced in 27 rats by streptozotocin, and the other 27 rats received buffer only. Ten weeks after induction of diabetes, both normal and diabetic rats were killed, their kidneys removed, and glomeruli were isolated. Glomeruli from normal and diabetic rats were incubated in the presence of TCF-beta1 alone or its neutralizing antibody. Antioxidant enzyme (Cu-Zn) superoxide dismutase (Cu-Zn SOD), catalase, and glutathione per oxidase (GSH-Px) activities; total glutathione; and lipid peroxidation were determined. Far Se studies, 15 normal and 15 diabetic rats were divided into groups of five each and fed either a regular, Se-deficient, or Se-supplemented diet one week after induction of diabetes. Ten weeks after feeding these diets, rats were killed and gromeruli were isolated. Oxidative stress was examined by determining the mRNA expressions for antioxidant enzymes and also for TGF-beta1. Plasma glucose and albuminuria were determined. Histology of the kidney and interlobular artery was evaluated by light microscopy.Results. In vitro studies showed that TGF-beta1 significantly reduced glomerular catalase and GSH-Px activities as well as total glutathione levels with an increase in lipid peroxidation in both normal and diabetic rats. Antibody to TGF-beta abrogated these changes. There was no effect of TGF-beta1 on Cu-Zn SOD. Like TGF-beta1, a Se-deficient diet caused a significant decrease in glomerular mRNA expression for Cu-Zn SOD, catalase, and GSH-Px, but a significant increase in TGF-beta1 mRNA expression. Also, a Se-deficient diet caused an increase in albuminuria, glomerular sclerosis, and plasma glucose levels in both normal and diabetic rats. The deficient diet caused a decrease in the lumen size of the interlobular artery. Se supplementation to diabetic rats up-regulated mRNA expression for antioxidant enzymes, and significantly reduced but did not normalize that of TGF-beta1. Glomerular sclerosis was normalized and the interlobular artery lumen size was greatly enlarged in diabetic rats by Se supplementation. Also, the tubulointerstitium was preserved by Se supplementation in diabetic rats.Conclusions. The data show that TGF-beta1 is a pro-oxidant and Se deficiency increases oxidative stress via this growth factor. In addition, Se deficiency may simulate hyperglycemic conditions. Se supplementation to diabetic rats prevents not only oxidative stress but renal structural injury, as well.