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Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor.
J Am Soc Nephrol. 2005 Sep; 16(9):2702-13.JA

Abstract

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-beta1-induced CTGF expression but also CTGF-induced collagen I (alpha1) [Col I (alpha1)] expression in normal rat kidney fibroblasts (NRK-49F) and alpha-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 (alpha1) 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-beta1-induced CTGF transcription, but PTX did not interfere with TGF-beta1 signaling to Smad2/3 activation and association with Smad4 and their nuclear translocation. However, PTX was capable of blocking activation of TGF-beta1-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.

Authors+Show Affiliations

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15987746

Citation

Lin, Shuei-Liong, et al. "Pentoxifylline Attenuates Tubulointerstitial Fibrosis By Blocking Smad3/4-activated Transcription and Profibrogenic Effects of Connective Tissue Growth Factor." Journal of the American Society of Nephrology : JASN, vol. 16, no. 9, 2005, pp. 2702-13.
Lin SL, Chen RH, Chen YM, et al. Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol. 2005;16(9):2702-13.
Lin, S. L., Chen, R. H., Chen, Y. M., Chiang, W. C., Lai, C. F., Wu, K. D., & Tsai, T. J. (2005). Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. Journal of the American Society of Nephrology : JASN, 16(9), 2702-13.
Lin SL, et al. Pentoxifylline Attenuates Tubulointerstitial Fibrosis By Blocking Smad3/4-activated Transcription and Profibrogenic Effects of Connective Tissue Growth Factor. J Am Soc Nephrol. 2005;16(9):2702-13. PubMed PMID: 15987746.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. AU - Lin,Shuei-Liong, AU - Chen,Ruey-Hwa, AU - Chen,Yung-Ming, AU - Chiang,Wen-Chih, AU - Lai,Chun-Fu, AU - Wu,Kwan-Dun, AU - Tsai,Tun-Jun, Y1 - 2005/06/29/ PY - 2005/7/1/pubmed PY - 2006/1/26/medline PY - 2005/7/1/entrez SP - 2702 EP - 13 JF - Journal of the American Society of Nephrology : JASN JO - J Am Soc Nephrol VL - 16 IS - 9 N2 - 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-beta1-induced CTGF expression but also CTGF-induced collagen I (alpha1) [Col I (alpha1)] expression in normal rat kidney fibroblasts (NRK-49F) and alpha-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 (alpha1) 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-beta1-induced CTGF transcription, but PTX did not interfere with TGF-beta1 signaling to Smad2/3 activation and association with Smad4 and their nuclear translocation. However, PTX was capable of blocking activation of TGF-beta1-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. SN - 1046-6673 UR - https://www.unboundmedicine.com/medline/citation/15987746/Pentoxifylline_attenuates_tubulointerstitial_fibrosis_by_blocking_Smad3/4_activated_transcription_and_profibrogenic_effects_of_connective_tissue_growth_factor_ L2 - https://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=15987746 DB - PRIME DP - Unbound Medicine ER -