Acta Pharmacologica Sinica (2009) 30: 98-106; doi: 10.1038/aps.2008.11; published online 15th December 2008

Inhibition of tubulointerstitial fibrosis by pentoxifylline is associated with improvement of vascular endothelial growth factor expression

Qiu-gen ZHOU¹, Fa-lei ZHENG^2,*, Fan-fan HOU^1,*

¹Division of Nephrology, Southern Medical University Nanfang Hospital, Guangzhou 510515, China; ²Division of Nephrology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China

Aim: Recent information indicates that pentoxifylline (PTX) has the ability to suppress inflammation and profibrotic cell proliferation. In this study, we investigated the effect of PTX on tubulointerstitial fibrosis and the expression of vascular endothelial growth factor (VEGF) in a rat model of obstructive nephropathy.

Methods: Wistar rats with left ureteral ligation were divided into control and PTX-treated groups. The histopathologic degree of tubulointerstitial fibrosis was scored with PAS and Masson-stained sections. The protein and mRNA for vascular endothelial growth factor (VEGF) were semiquantitatively measured with immunohistochemistry and RT-PCR. The protein for transforming growth factor β1 (TGFβ1) and hypoxia-induced factor 1 alpha (HIF-1α) was determined by Western blot.

Results: Compared with the control group, PTX treatment reduced fibrosis scores at d 7 and d 14 (P<0.05).  The reduction was accompanied by inhibited expression of transforming growth factor-beta 1 (TGFβ1), a key cytokine in tubulointerstitial fibrogenesis (P<0.01).  Meanwhile, VEGF protein and mRNA in the kidney were increased in the PTX-treated group compared with the control group (P<0.01).  PTX up-regulated expression of VEGF mRNA in a dose- and time-dependent manner in cultured HK-2 cells (P<0.01).  However, expression of HIF-1α (a key transcription factor for VEGF gene expression) was unchanged by PTX treatment.  PTX prolonged the half-life of VEGF mRNA by a 1.07-fold increase. 

Conclusions: PTX inhibited tubulointerstitial fibrosis in a rat model of obstructive nephropathy while preventing loss of VEGF. PTX up-regulated expression of VEGF mRNA through stabilization of its mRNA in cultured renal tubular epithelial cells.

Keywords: tubulointerstitial fibrosis; vascular endothelial growth factor; pentoxifylline