Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-beta/Smad activity

Lab Invest. 2010 Mar;90(3):436-47. doi: 10.1038/labinvest.2009.149. Epub 2010 Feb 8.

Abstract

Transforming growth factor-beta (TGF-beta) has a pivotal function in the progression of renal fibrosis in a wide variety of renal diseases. Smad proteins have been identified to have an important function in regulating the expression of extracellular matrix (ECM) proteins through TGF-beta signaling pathway. Aberrant TGF-beta/Smad signaling can be modulated by stabilization of microtubules with paclitaxel. In this study, we investigated if paclitaxel can attenuate tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction (UUO). Rats in groups of six were subjected to UUO and received low-dose intraperitoneal injection of paclitaxel (0.3 mg/kg) twice a week. They were killed at day 7 and 14 after UUO or Sham operation. TGF-beta signaling cascade and status of various ECM proteins were evaluated by RT-PCR, western blotting and immunohistochemical or immunofluorescence staining. The paclitaxel treatment markedly suppressed Smad2 and Smad3 phosphorylation. This was associated with attenuated expression of integrin-linked kinase, collagens I and III, fibronectin (FN) and alpha-smooth muscle actin, and a substantial decrease in renal fibrosis in animals that underwent UUO and received paclitaxel. These data indicate that the low-dose paclitaxel ameliorates renal tubulointerstitial fibrosis by modulating TGF-beta signaling, and thus, the paclitaxel may have some therapeutic value in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Extracellular Matrix / metabolism
  • Kidney / pathology
  • Male
  • Nephrosclerosis / etiology
  • Nephrosclerosis / pathology
  • Nephrosclerosis / prevention & control*
  • Paclitaxel / pharmacology
  • Paclitaxel / therapeutic use*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Smad Proteins / antagonists & inhibitors*
  • Transforming Growth Factor beta / antagonists & inhibitors*
  • Tubulin Modulators / pharmacology
  • Tubulin Modulators / therapeutic use*
  • Ureteral Obstruction / complications

Substances

  • Smad Proteins
  • Transforming Growth Factor beta
  • Tubulin Modulators
  • Paclitaxel