Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-β1 transgenic mice
Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-β1 transgenic mice
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DOI：
10.1172/jci119815
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发表时间：
1997-12-01
影响因子：
15.9
通讯作者：
Hammer, RE
中科院分区：
文献类型：
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作者：
Clouthier, DE;Comerford, SA;Hammer, RE
在大鼠磷酸烯醇丙酮酸羧激酶调控序列的控制下，转基因小鼠过度表达构成活性的人tgf - β 1，导致肝脏、肾脏和脂肪组织纤维化，并表现出体内脂肪的严重减少。肝细胞中转基因的表达导致胶原沉积增加，小叶组织改变，肝细胞更新增加，在极端情况下，出血和血栓形成。该基因在肾脏的表达定位于近端小管上皮，并与小管间质纤维化有关，其特征是胶原沉积过多，纤维连接蛋白和纤溶酶原激活物抑制剂-1免疫反应性增高，肾小球硬化明显，肾水肿发生率低，白色和棕色脂肪组织中tgf - β 1的表达导致脂肪营养不良样综合征。所有白色脂肪库和棕色脂肪垫的大小都严重减少，并表现出明显的纤维增生，这种WAT的减少是由于脂肪堆积受损，将转基因引入ob/ob背景抑制了该突变的肥胖特征；这些研究加强了tgf - β 1表达与纤维化疾病之间的联系，并证明了tgf - β 1在体内调节间充质细胞分化的效力。
Transgenic mice overexpressing a constitutively active human TGF-beta 1 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-beta 1 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-beta 1 expression and fibrotic disease, and demonstrate the potency of TGF-beta 1 in modulating mesenchymal cell differentiation in vivo.