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Pentoxifylline Attenuates Tubulointerstitial Fibrosis by Blocking Smad3/4-Activated Transcription and Profibrogenic Effects of Connective Tissue Growth Factor

Shuei-Liong Lin^*,, Ruey-Hwa Chen, Yung-Ming Chen^*,, Wen-Chih Chiang^*,, Chun-Fu Lai^*, Kwan-Dun Wu^*, and Tun-Jun Tsai^*,

^* Department of Internal Medicine, National Taiwan University Hospital, and Department of Medicine, Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Address correspondence to: Dr. Tun-Jun Tsai, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan 100. Phone: 886-2-23123456 ext. 3953; Fax: 886-2-23222955; E-mail: paul{at}ha.mc.ntu.edu.tw

Received for publication April 27, 2005. Accepted for publication June 7, 2005.

Pentoxifylline (PTX) is a potent inhibitor of connective tissue growth factor (CTGF), but its underlying mechanism is poorly understood. Here, it was demonstrated that PTX inhibited not only TGF-1–induced CTGF expression but also CTGF-induced collagen I (1) [Col I (1)] expression in normal rat kidney fibroblasts (NRK-49F) and -smooth muscle actin expression in normal rat kidney proximal tubular epithelial cells (NRK-52E). Furthermore, PTX attenuated tubulointerstitial fibrosis, myofibroblasts accumulation, and expression of CTGF and Col I (1) in unilateral ureteral obstruction kidneys. The mechanism by which PTX reduced CTGF in NRK-49F and NRK-52E was investigated. Activation of Smad3/4 was essential for TGF-1–induced CTGF transcription, but PTX did not interfere with TGF-1 signaling to Smad2/3 activation and association with Smad4 and their nuclear translocation. However, PTX was capable of blocking activation of TGF-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. It was found that PTX increased intracellular cAMP and caused cAMP response element binding protein phosphorylation. The protein kinase A 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, these results indicate that PTX inhibits CTGF expression by interfering with Smad3/4-dependent CTGF transcription through protein kinase A and blocks the profibrogenic effects of CTGF on renal cells. Because of the dual blockade, PTX potently attenuates the tubulointerstitial fibrosis in unilateral ureteral obstruction kidneys.

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