Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor
Journal
Journal of the American Society of Nephrology
Journal Volume
16
Journal Issue
9
Pages
2702-2713
Date Issued
2005
Author(s)
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-β1-induced CTGF expression but also CTGF-induced collagen I (α1) [Col I (α1)] expression in normal rat kidney fibroblasts (NRK-49F) and α-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 (α1) 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-β1-induced CTGF transcription, but PTX did not interfere with TGF-β1 signaling to Smad2/3 activation and association with Smad4 and their nuclear translocation. However, PTX was capable of blocking activation of TGF-β1-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. Copyright ? 2005 by the American Society of Nephrology.
SDGs
Other Subjects
alpha smooth muscle actin; bucladesine; cancer growth factor; collagen type 1; collagen type 1 alpha; connective tissue growth factor; cyclic AMP; cyclic AMP dependent protein kinase inhibitor; forskolin; pentoxifylline; Smad3 protein; Smad4 protein; unclassified drug; actin; angiotensin II; immediate early protein; Madh3 protein, rat; Madh4 protein, rat; signal peptide; Smad3 protein; Smad4 protein; Tgfb1 protein, rat; transforming growth factor beta; transforming growth factor beta1; animal cell; animal experiment; article; drug antagonism; drug inhibition; drug mechanism; gene expression; kidney artery stenosis; kidney epithelium; kidney fibrosis; male; myofibroblast; nonhuman; priority journal; protein binding; protein phosphorylation; rat; animal; biological model; biosynthesis; cell line; drug effect; fibrosis; genetics; kidney; metabolism; pathology; signal transduction; transactivation; ureter obstruction; Wistar rat; Actins; Angiotensin II; Animals; Cell Line; Collagen Type I; Fibrosis; Gene Expression; Immediate-Early Proteins; Intercellular Signaling Peptides and Proteins; Kidney; Male; Models, Biological; Pentoxifylline; Rats; Rats, Wistar; Signal Transduction; Smad3 Protein; Smad4 Protein; Trans-Activation (Genetics); Transforming Growth Factor beta; Transforming Growth Factor beta1; Ureteral Obstruction
Type
journal article