林水龍2006-07-262018-07-112006-07-262018-07-112005http://ntur.lib.ntu.edu.tw//handle/246246/23697Pentoxifylline(PTX)為結締組織生長因子(CTGF)的強利抑制劑，但抑制機轉並不清楚。 本研究不僅證實PTX 可以抑制轉化生長因子β1(TGF-β1)誘發CTGF 的表現，也證實PTX 可 以抑制NRK-49F 纖維母細胞表現第一型膠元蛋白與NRK-52E 近端腎小管上皮細胞表現α- smooth muscle actin(α-SMA)。進一步的研究發現Smad3/4 的活化為TGF-β1 誘發CTGF 基因轉錄所必須，雖然PTX 無法干擾TGF-β1 活化Smad2/3 及其與Smad4 的結合及後續的移位至 細胞核內，但PTX 可以抑制TGF-β1 刺激Smad3/4 所活化的reporter ，也可以抑制CTGF 的 promoter 的活化。因此吾人推測PTX 可能經由干擾與Smad3/4 協同刺激CTGF 轉錄的分子以達 到抑制CTGF 的表現。吾人進一步證實PTX 經由增加細胞內cyclic adenine monophosphate (cAMP)以活化蛋白質磷酸化脢A(PKA)，而PKA 的抑制劑H89 可以逆轉PTX 抑制CTGF 轉錄的 作用，但 dibutyryl cAMP 及forskolin 可以造成與PTX 相同的作用。因此吾人結論:PTX 透過活 化PKA 以抑制TGF-β1 刺激Smad3/4 所活化的CTGF 轉錄並進一步抑制CTGF 促進腎臟細胞產 生纖維化的作用。Pentoxifylline (PTX) is a potent inhibitor of connective tissue growth factor (CTGF), but its underlying mechanism is poorly understood. Here, we demonstrated that PTX inhibited not only transforming growth factor-β 1 (TGF- β 1)-induced CTGF expression, but also CTGF-induced collagen I (1) [Col I (1)] expression in NRK-49F and α -smooth muscle actin expression in NRK-52E cells. The mechanism by which PTX reduced CTGF in NRK-49F and NRK-52E was investigated. Activation of Smad3/4 was essential for TGF-β 1-induced CTGF transcription, but PTX did not interfere with TGF-β 1 signaling to Smad2/3 activation, association with Smad4, and their nuclear translocation. However, PTX was capable of blocking activation of TGF-β 1-induced Smad3/4-dependent reporter as well as CTGF promoter, suggesting that PTX affects a factor that acts cooperatively with Smad3/4 to execute transcriptional activation. We found that PTX increased intracellular cyclic adenine monophosphate (cAMP) and caused cAMP response element binding protein phosphorylated. The protein kinase A (PKA) antagonist H89 abolished the inhibitory effect of PTX on Smad3/4-dependent CTGF transcription, whereas dibutyryl cAMP and forskolin recapitulated the inhibitory effect. In conclusion, our results indicate that PTX inhibits CTGF expression by interfering with Smad3/4-dependent CTGF transcription through PKA and blocks the profibrogenic effects of CTGF on renal cells.application/pdf3743922 bytesapplication/pdfzh-TW國立臺灣大學醫學院內科Pentoxifylline結締組織生長因子上皮間質轉分化Smad轉化生長因子β1connective tissue growth factorepithelial-mesenchymal transdifferentiationtransforming growth factor-β1reporthttp://ntur.lib.ntu.edu.tw/bitstream/246246/23697/1/932314B002144.pdf