PENTOXIFYLLINE INHIBITS TRANSFORMING GROWTH FACTOR-BETA SIGNALING AND RENAL FIBROSIS IN EXPERIMENTAL CRESCENTIC GLOMERULONEPHRITIS IN RATS

Background/Aims: 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-beta 1 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-beta 1 expression and Smad2/3 activation may be a mechanism by which PTX inhibits renal fibrosis