Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury.
Overexpression of upstream stimulatory factor 2 accelerates diabetic kidney injury.
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上游刺激因子 2 的过度表达会加速糖尿病肾损伤。
DOI：
10.1152/ajprenal.00316.2007
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Wang,Shuxia
中科院分区：
文献类型：
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作者：
Liu,Shu;Shi,Lihua;Wang,Shuxia
糖尿病肾病是美国最常见的终末期肾衰竭的原因。高血压是糖尿病肾病发病的重要因素。高血糖可上调转化生长因子-β（TGF-β）的表达，从而刺激细胞外基质在肾脏中沉积，促进糖尿病肾病的发展。我们的前期研究表明，高糖可上调转录因子上游刺激因子2（upstream stimulatory factor 2，USF 2）的表达，USF 2与血小板反应蛋白1（thrombospondin 1，TSP 1）基因启动子区的18 bp序列结合，调节高糖诱导的系膜细胞TSP 1表达和TGF-β活性，提示USF 2可能在糖尿病肾病的发生发展中发挥作用。在目前的研究中，我们研究了USF 2过表达对糖尿病肾病发展的影响。通过注射链脲佐菌素在USF 2转基因小鼠[USF 2（Tg）]及其野生型同窝小鼠（WT）中诱导1型糖尿病。研究了四组小鼠：对照WT、对照USF 2（Tg）、糖尿病WT和糖尿病USF 2（Tg）。糖尿病发病15周后处死小鼠。在研究结束时，对照USF 2（Tg）小鼠（1.66月龄）表现出尿白蛋白排泄增加。与对照WT同窝小鼠相比，这些小鼠还表现出肾小球肥大，伴随肾小球中TSP 1、活性TGF-β、纤连蛋白蓄积增加。1型糖尿病发作进一步增加了USF 2（Tg）小鼠的尿白蛋白排泄和肾小球肥大。这些发现表明USF 2的过度表达加速了糖尿病肾病的发展。
Diabetic nephropathy is the most common cause of end-stage renal failure in the United States. Hyperglycemia is an important factor in the pathogenesis of diabetic nephropathy. Hyperglycemia upregulates the expression of transforming growth factor-β (TGF-β), which stimulates extracellular matrix deposition in the kidney, contributing to the development of diabetic nephropathy. Our previous studies demonstrated that the transcription factor, upstream stimulatory factor 2 (USF2), was upregulated by high glucose, which bound to an 18-bp sequence in the thrombospondin 1 (TSP1) gene promoter and regulated high glucose-induced TSP1 expression and TGF-β activity in mesangial cells, suggesting that USF2 might play a role in the development of diabetic nephropathy. In the present studies, we examined the effect of overexpression of USF2 on the development of diabetic nephropathy. Type 1 diabetes was induced in USF2 transgenic mice [USF2 (Tg)] and their wild-type littermates (WT) by injection of streptozotocin. Four groups of mice were studied: control WT, control USF2 (Tg), diabetic WT, and diabetic USF2 (Tg). Mice were killed after 15 wk of diabetes onset. At the end of studies, control USF2 (Tg) mice (∼6 mo old) exhibited increased urinary albumin excretion. These mice also exhibited glomerular hypertrophy, accompanied by increased TSP1, active TGF-β, fibronectin accumulation in the glomeruli compared with control WT littermates. Type 1 diabetes onset further augmented the urinary albumin excretion and glomerular hypertrophy in the USF2 (Tg) mice. These findings suggest that overexpression of USF2 accelerates the development of diabetic nephropathy.