Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy
Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy
复制标题
DOI：
10.1016/s0006-291x(03)00885-4
复制
发表时间：
2003-06-13
影响因子：
3.1
通讯作者：
Mori, S
中科院分区：
文献类型：
--
作者：
Fujimoto, M;Maezawa, Y;Mori, S
转化生长因子-β（TGF-β）与糖尿病性肾小球病的发生有关。为了评估Smad 3（TGF-β下游的主要信号传导分子之一）在糖尿病性肾小球病发病机制中的作用，用链脲佐菌素注射使Smad 3缺失小鼠患糖尿病，并在诱导糖尿病后4周进行分析。电子显微镜显示，肾小球基底膜（GBM）的厚度在野生型糖尿病小鼠明显高于非糖尿病小鼠，而没有明显的GBM增厚Smad 3-null糖尿病小鼠被发现。野生型糖尿病小鼠的尿白蛋白排泄显著增加，而Smad 3基因缺失的糖尿病小鼠未显示任何明显的白蛋白尿。北方印迹显示，野生型糖尿病小鼠肾皮质中的纤连蛋白和IV型胶原α 3链（α 3 Col 4）的mRNA水平约为非糖尿病小鼠的两倍，而Smad 3缺失型糖尿病小鼠中它们的mRNA水平没有增加。实时聚合酶链反应（PCR）也证实了糖尿病诱导的野生型小鼠肾小球中纤连蛋白和α 3Col 4的上调。通过实时PCR评估，野生型和Smad 3缺失型糖尿病小鼠的TGF-β 1肾小球表达增强到相似的程度，表明野生型和Smad 3缺失型小鼠之间观察到的差异并不归因于TGF-β 1表达的差异。这些数据清楚地证明了Smad 3在糖尿病性肾小球病的早期阶段中的关键作用。这可能至少部分是由于目前的发现，即糖尿病诱导的纤连蛋白和α 3Col 4的上调依赖于Smad 3功能。(C)2003 Elsevier Science（美国）。All rights reserved.
Transforming growth factor-beta (TGF-beta) has been implicated in the development of diabetic glomerulopathy. In order to evaluate a role of Smad3, one of the major signaling molecules downstream of TGF-beta, in the pathogenesis of diabetic glomerulopathy, Smad3-null mice were made diabetic with streptozotocin injection and analyzed 4 weeks after induction of diabetes. Electron microscopy revealed that the thickness of glomerular basement membrane (GBM) in wild-type diabetic mice was significantly higher than that in non-diabetic mice, whereas no appreciable GBM thickening was found in Smad3-null diabetic mice. Urinary albumin excretion was dramatically increased in wild-type diabetic mice, whereas Smad3-null diabetic mice did not show any overt albuminuria. Northern blotting revealed that mRNA levels of fibronectin and alpha3 chain of type IV collagen (alpha3Col4) in renal cortex of wild-type diabetic mice were approximately twice as much as those of non-diabetic mice, whereas their mRNA levels were not increased in Smad3-null diabetic mice. Real-time polymerase chain reaction (PCR) also confirmed diabetes-induced upregulation of fibronectin and alpha3Col4 in glomeruli of wild-type mice. Glomerular expression of TGF-beta1, as assessed by real-time PCR, was enhanced to a similar degree in wild-type and smad3-null diabetic mice, indicating that the observed differences between wild-type and Smad3-null mice are not attributable to difference in the expression of TGF-beta1. These data clearly demonstrate a critical role of Smad3 in the early phase of diabetic glomerulopathy. This may be due at least partly to the present findings that diabetes-induced upregulation of fibronectin and alpha3Col4 is dependent on Smad3 function. (C) 2003 Elsevier Science (USA). All rights reserved.