Lowden D A, Lindemann G W, Merlino G, Barash B D, Calvet J P, Gattone V H
Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City 66160-7400.
J Lab Clin Med. 1994 Sep;124(3):386-94.
Transforming growth factor-alpha (TGF-alpha) is a member of the epidermal growth factor (EGF) family of proteins and, like EGF, elicits its cellular function by binding to the EGF receptor. EGF stimulation may have a role in several normal and pathologic processes in the kidney, and EGF has been implicated in the development of renal cysts in vitro and in human autosomal dominant polycystic kidney disease. We sought to determine whether renal expression of an EGF-like protein (TGF-alpha) could lead to the formation of renal cysts in vivo. We examined morphologic alterations to the normal kidney caused by renal expression of a TGF-alpha transgene linked to a mouse metallothionein promoter stably integrated into the genome of the CD1 mouse. TGF-alpha transgene expression was induced with exogenous zinc treatment starting at 4 weeks of age, and mice were killed at 8 weeks of age. The transgene was expressed at higher levels in female transgenic mice than in male transgenic mice. The augmented expression of the TGF-alpha transgene in females was associated with increased renal size and the development of renal epithelial cysts. Both male and female mice exhibited increases in glomerular size and mesangial volume density. These results provide evidence that stimulation by an endogenous EGF-like protein can lead to renal enlargement, glomerular mesangial expansion, and renal cyst formation.
转化生长因子-α（TGF-α）是表皮生长因子（EGF）蛋白家族的成员，与EGF一样，它通过与EGF受体结合来发挥其细胞功能。EGF刺激可能在肾脏的多种正常和病理过程中起作用，并且EGF已被证明在体外以及人类常染色体显性多囊肾病中与肾囊肿的形成有关。我们试图确定一种EGF样蛋白（TGF-α）的肾脏表达是否会在体内导致肾囊肿的形成。我们研究了与稳定整合到CD1小鼠基因组中的小鼠金属硫蛋白启动子相连的TGF-α转基因在肾脏中的表达所引起的正常肾脏的形态学改变。从4周龄开始用外源性锌处理诱导TGF-α转基因表达，在8周龄时处死小鼠。转基因在雌性转基因小鼠中的表达水平高于雄性转基因小鼠。雌性中TGF-α转基因表达的增加与肾脏大小增加和肾上皮囊肿的形成有关。雄性和雌性小鼠均表现出肾小球大小和系膜体积密度增加。这些结果提供了证据，表明内源性EGF样蛋白的刺激可导致肾脏增大、肾小球系膜扩张和肾囊肿形成。
