Paclitaxel attenuates renal interstitial fibroblast activation and interstitial fibrosis by inhibiting STAT3 signaling

Lei Zhang, Xuan Xu, Ruhao Yang, Jingwen Chen, Shixuan Wang, Junqin Yang, Xudong Xiang, Zhibiao He, Yu Zhao, Zheng Dong, Dongshan Zhang

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Recent studies have demonstrated that paclitaxel might inhibit renal fibrosis. However, the underlying molecular mechanism remains unclear. In this study, we hypothesized that low-dose paclitaxel may block the STAT3 (signal transducer and activator of transcription 3) signaling to attenuate fibrosis in a mouse model with unilateral ureteral obstruction. Both NRK-49F cells and mice with unilateral ureteral obstruction were treated with paclitaxel. The results showed that paclitaxel treatment resulted in a dose- and time-dependent decrease in tyrosine-phosphorylated STAT3, and inhibited the expression of fibronectin, alpha-smooth muscle actin (α-SMA), and collagen I in cultured NRK-49F cells. S3I-201, an STAT3 inhibitor, also suppressed the expression of fibronectin, α-SMA, and collagen I in cultured NRK-49F cells. Mechanistically, paclitaxel treatment blocked the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation. Furthermore, paclitaxel also ameliorated renal fibrosis by down-regulating the expression of fibronectin, α-SMA, and collagen I, and suppressed the infiltration of macrophages and production of TNF-a, IL-1β, TGF-β, and ICAM-1 (intercellular adhesion molecule 1) by inhibition of STAT3 activity in obstructive nephropathy. These results suggest that paclitaxel may block the STAT3 activity by disrupting the association of STAT3 with tubulin and inhibiting STAT3 nucleus translocation, consequently leading to the suppression of renal interstitial fibroblast activation and the development of renal fibrosis, and inhibition of proinflammatory cytokine production.

Original languageEnglish (US)
Pages (from-to)2139-2148
Number of pages10
JournalDrug Design, Development and Therapy
Volume9
DOIs
StatePublished - Mar 15 2015

    Fingerprint

Keywords

  • Paclitaxel
  • STAT3
  • Tubulin
  • Tubulointerstitial fibrosis
  • UUO

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery

Cite this