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

Dongshan Zhang, Lin Sun, Wang Xian, Fuyou Liu*, Guanghui Ling, Li Xiao, Yanhong Liu, Youmin Peng, Yoshisuke Haruna, Yashpal S. Kanwar

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Transforming growth factor-Β (TGF-Β) 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-Β signaling pathway. Aberrant TGF-Β/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-Β 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 α-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-Β signaling, and thus, the paclitaxel may have some therapeutic value in humans.

Original languageEnglish (US)
Pages (from-to)436-447
Number of pages12
JournalLaboratory Investigation
Volume90
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • Microtubule
  • Paclitaxel
  • Smad
  • TGF-β
  • Tubulointerstitial fibrosis
  • UUO

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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