Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy
Overexpression of thioredoxin1 in transgenic mice suppresses development of diabetic nephropathy
复制标题
DOI：
10.1093/ndt/gfm099
复制
发表时间：
2007-06-01
影响因子：
6.1
通讯作者：
Kasuga, Masato
中科院分区：
文献类型：
--
作者：
Hamada, Yasuhiro;Miyata, Satoshi;Kasuga, Masato
背景资料。氧化应激在糖尿病肾病的发病机制中起重要作用。本研究利用TRX1转基因小鼠(TRX1-TG)研究了具有抗氧化功能的小蛋白--硫氧还蛋白1(TRX1)过表达对链脲佐菌素诱导的糖尿病大鼠糖尿病肾病的影响。8周龄雄性TRX1-TG小鼠和野生型小鼠(WT)分别给予链脲佐菌素(200 mg/kg)或单纯赋形剂治疗。治疗24周后，通过血液和尿液的生化分析以及肾脏的组织学分析，评估这四组小鼠的糖尿病肾病和氧化应激。糖尿病患者的糖化血红蛋白(HbA1c)水平与糖尿病WT组无显著差异。然而，在糖尿病WT中观察到的尿白蛋白排泄增加在糖尿病TRX1-TG中显著减少。组织学研究显示，与糖尿病WT组相比，糖尿病组大鼠肾小球系膜基质扩张、肾小管损伤等病理改变明显减少，转化生长因子-P表达降低。同时，糖尿病WT组小鼠尿8-羟基-2‘-脱氧鸟苷和丙烯醛加合物排泄量及肾脏中这些标志物的免疫染色强度显著高于非糖尿病小鼠。这些标记物在糖尿病患者TRX1-TG中显著抑制，这是由于TRX1过表达而导致全身和肾脏氧化应激减弱的一个指标。这些发现表明氧化应激在糖尿病肾病的发生发展中起着重要作用，TRX1有可能抑制肾病的进展。
Background. Oxidative stress has been suggested to play an important role in the pathogenesis of diabetic nephropathy. In the present study, the effects of thioredoxin1 (TRX1) overexpression, a small protein with antioxidant property, on the development of diabetic nephropathy in streptozotocin-induced diabetic animals were investigated using TRX1 transgenic mice (TRX1-Tg).Methods. Eight-week-old male TRX1-Tg and wildtype mice littermates (WT) mice were treated either with streptozotocin (200 mg/kg) or vehicle alone. After 24 weeks of treatment, diabetic nephropathy and oxidative stress were assessed in these four groups of mice, by biochemical analyses of blood and urine, as well as by histological analyses of the kidneys.Results. Haemoglobin A1c (HbA1c) levels of diabetic TRX1-Tg were not significantly different from those of the diabetic WT. Nevertheless, an augmented urinary albumin excretion observed in diabetic WT was significantly diminished in diabetic TRX1-Tg. Histological study revealed that pathological changes such as mesangial matrix expansion and tubular injury were significantly prevented in diabetic TRX1-Tg accompanied by a reduced tendency of expression of transforming growth factor-P as compared wit diabetic WT. In parallel, urinary excretion of 8-hydroxy-2'-deoxyguanosine and acrolein adduct and the immunostaining intensities of these markers in the kidney were significantly higher in diabetic WT compared with non-diabetic mice. The markers were significantly suppressed in diabetic TRX1-Tg, an indication of systemic and renal oxidative stress attenuation by TRX1 overexpression.Conclusion. These findings indicated the significant role of oxidative stress in the development of diabetic nephropathy and a potential inhibition of progression of nephropathy by TRX1.