REGULATION OF TGF-β AND ITS SIGNAL MOLECULE, SMAD FOR ATTENUATION OF PERITONEAL FIBROSIS.

转化生长因子-β-1在包括腹膜纤维化在内的纤维化和硬化性疾病中起病理作用。Smads已被认为是转化生长因子-**细胞内信号转导的关键成分。本研究旨在探讨转化生长因子-β对培养细胞和实验性腹膜纤维性疾病的诱导作用。有教养的人！细胞，转化生长因子-β-1诱导Smad2的磷酸化；腺病毒载体基因转移，Smad2和Smad4的双过表达诱导转化生长因子-I3诱导的纤溶酶原激活物抑制物-1(PM-I)的表达高于单独Smad2的过表达。此外，抑制Smad的Smad7的过表达，而不是Smd6的过表达，逆转了转化生长因子-β1-通过抑制Smad2的磷酸化而抑制细胞的增殖。此外，转化生长因子-β-1或高糖条件下可诱导Smad2结合元件荧光素酶活性的表达，而Smad2突变型或内源性Smad7可逆转Smad2-荧光素酶活性。这一厚度是由于基质蛋白的积累造成的。我们尝试将Smad蛋白基因转移到这些动物模型中。但是腹膜！纤维化是不可复制的。我们现在正在研究制作可复制的腹膜纤维化模型。然而，我们的结果表明，Smad活性的调节可能会减缓腹膜纤维化和硬化的发展。

TGF-β1 plays a pathological role in fibrotic and sclerotic diseases including peritoneal fibrosis. Smads have been identified as pivotal components in TGF-** intracellular signaling. The present study was carried out to investigate TGF-β-induced Smad activation in cultured cells and experimental peritoneal firotic diseases in rodents. In cultured! cells, TGF-β1 induced phosphorylation of Smad2.Gene transfer using Adenovirus-vector, double-overexpression of Smad2 and Smad4 induced TGF-I3istimulated plasminogen activator inhibitor-1 (PM-i) expression more than overexpression of each Smad alone. Furthermore, overexpression of Smad7, one of inhibitory Smads, but not Smd6 reversed TGF- β1-inhibited cell proliferation by inhibiting Smad2 phosphorylation. In addition, TGF-β1 or high glucose condition induced the expression of SBE (Smad-binding element)-luciferase activity, which was reversed by the transfection-with Smad2 mutant or inhitory Smad7.In experimental peritoneal fibrosis using iodine, progressive peritoneal thickness was observed. This thickness was due to the accumulation of matrix proteins. We tried gene transfer of Smad protein into these animal models. But the peritonea! fibrosis was not reproducible. We are now under investigation to make reproducible model of peritoneal fibrosis. However, our results indicate the possibility that modulation of Smad activity may attenuate the development of peritoneal fibrosis and sclerosis.