Clouthier D E, Comerford S A, Hammer R E
Department of Biochemistry and the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9050, USA.
J Clin Invest. 1997 Dec 1;100(11):2697-713. doi: 10.1172/JCI119815.
Transgenic mice overexpressing a constitutively active human TGF-beta1 under control of the rat phosphoenolpyruvate carboxykinase regulatory sequences developed fibrosis of the liver, kidney, and adipose tissue, and exhibited a severe reduction in body fat. Expression of the transgene in hepatocytes resulted in increased collagen deposition, altered lobular organization, increased hepatocyte turnover, and in extreme cases, hemorrhage and thrombosis. Renal expression of the transgene was localized to the proximal tubule epithelium, and was associated with tubulointerstitial fibrosis, characterized by excessive collagen deposition and increased fibronectin and plasminogen activator inhibitor-1 immunoreactivity. Pronounced glomerulosclerosis was evident, and hydronephrosis developed with low penetrance. Expression of TGF-beta1 in white and brown adipose tissue resulted in a lipodystrophy-like syndrome. All white fat depots and brown fat pads were severely reduced in size, and exhibited prominent fibroplasia. This reduction in WAT was due to impaired adipose accretion. Introduction of the transgene into the ob/ob background suppressed the obesity characteristic of this mutation; however, transgenic mutant mice developed severe hepato- and splenomegaly. These studies strengthen the link between TGF-beta1 expression and fibrotic disease, and demonstrate the potency of TGF-beta1 in modulating mesenchymal cell differentiation in vivo.
在大鼠磷酸烯醇丙酮酸羧激酶调控序列控制下过表达组成型活性人转化生长因子β1（TGF-β1）的转基因小鼠出现了肝脏、肾脏和脂肪组织的纤维化，并表现出体脂严重减少。转基因在肝细胞中的表达导致胶原沉积增加、小叶结构改变、肝细胞更新加快，在极端情况下还会出现出血和血栓形成。转基因在肾脏中的表达定位于近端小管上皮，与肾小管间质纤维化有关，其特征是胶原过度沉积以及纤连蛋白和纤溶酶原激活物抑制剂-1免疫反应性增加。明显的肾小球硬化很明显，肾积水以低发生率出现。TGF-β1在白色和棕色脂肪组织中的表达导致了类似脂肪营养不良的综合征。所有白色脂肪库和棕色脂肪垫的大小都严重减小，并表现出明显的纤维组织增生。白色脂肪组织的这种减少是由于脂肪蓄积受损。将转基因导入ob/ob背景抑制了该突变的肥胖特征；然而，转基因突变小鼠出现了严重的肝肿大和脾肿大。这些研究加强了TGF-β1表达与纤维化疾病之间的联系，并证明了TGF-β1在体内调节间充质细胞分化的效力。
