Pentoxifylline inhibits transforming growth factor-beta signaling and renal fibrosis in experimental crescentic glomerulonephritis in rats.
OBJECTIVE
Pentoxifylline (PTX) has been shown to inhibit renal inflammation in a rat model of crescentic glomerulonephritis. The present study investigated the role of PTX in renal fibrosis in rats with crescentic glomerulonephritis.


METHODS
A rat model of accelerated anti-glomerular basement membrane glomerulonephritis was induced and treated with PTX or vehicle control for 3, 7, 14 and 28 days. The therapeutic effect and mechanism of PTX on renal fibrosis were examined by Northern blot and immunohistochemistry.


RESULTS
Diseased rats treated with vehicle control developed a severe crescentic glomerulonephritis with progressive renal fibrosis identified by a marked accumulation of alpha-SMA+ myofibroblasts and collagen matrix. This was associated with tubular epithelial-myofibroblast transition as evident by de novo expression of alpha-SMA and a loss of E-cadherin on damaged tubular epithelial cells. Further studies revealed that severe renal fibrosis was associated with upregulation of renal TGF-beta1 and activation of TGF-beta/Smad signaling, which was blocked by treatment with PTX.


CONCLUSIONS
PTX may be an anti-fibrosis agent capable of inhibiting renal fibrosis in a rat model of crescentic glomerulonephritis. Blockade of TGF-beta1 expression and Smad2/3 activation may be a mechanism by which PTX inhibits renal fibrosis.
Ng
Yee-Yung
YY
Section of Nephrology, Department of Medicine, Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang Ming University, Taipei, Taiwan.
Chen
Yung-Ming
YM
Tsai
Tun-Jun
TJ
Lan
Xiao-Ru
XR
Yang
Wu-Chang
WC
Lan
Hui Y
HY
D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D005921:Glomerulonephritis / Q000378:metabolism*; D007668:Kidney / Q000473:pathology*; D008297:Male; D008954:Models, Biological; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D010726:Phosphodiesterase Inhibitors; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D010431:Pentoxifylline