Pentoxifylline治療腎小管間質纖維化

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.