Hamada Yasuhiro, Miyata Satoshi, Nii-Kono Tomoko, Kitazawa Riko, Kitazawa Sohei, Higo Satomi, Fukunaga Michiru, Ueyama Shigemitu, Nakamura Hajime, Yodoi Junji, Fukagawa Masafumi, Kasuga Masato
Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Nephrol Dial Transplant. 2007 Jun;22(6):1547-57. doi: 10.1093/ndt/gfm099. Epub 2007 Mar 14.
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).
Eight-week-old male TRX1-Tg and wild-type 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.
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-beta as compared with 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.
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.
氧化应激被认为在糖尿病肾病的发病机制中起重要作用。在本研究中，使用硫氧还蛋白1（TRX1）转基因小鼠（TRX1-Tg）研究了具有抗氧化特性的小蛋白TRX1过表达对链脲佐菌素诱导的糖尿病动物糖尿病肾病发展的影响。
对8周龄雄性TRX1-Tg小鼠和野生型同窝小鼠（WT）分别给予链脲佐菌素（200mg/kg）或单独给予载体。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，对这四组小鼠的糖尿病肾病和氧化应激进行评估。
糖尿病TRX1-Tg小鼠的糖化血红蛋白（HbA1c）水平与糖尿病WT小鼠无显著差异。然而，糖尿病WT小鼠中观察到的尿白蛋白排泄增加在糖尿病TRX1-Tg小鼠中显著减少。组织学研究表明，与糖尿病WT小鼠相比，糖尿病TRX1-Tg小鼠中系膜基质扩张和肾小管损伤等病理变化得到显著预防，同时转化生长因子-β的表达趋势降低。同时，与非糖尿病小鼠相比，糖尿病WT小鼠中8-羟基-2'-脱氧鸟苷和丙烯醛加合物的尿排泄以及这些标志物在肾脏中的免疫染色强度显著更高。这些标志物在糖尿病TRX1-Tg小鼠中显著受到抑制，表明TRX1过表达可减轻全身和肾脏的氧化应激。
这些发现表明氧化应激在糖尿病肾病发展中起重要作用，并且TRX1可能对肾病进展具有潜在的抑制作用。
