Low-dose paclitaxel ameliorates renal fibrosis by suppressing transforming growth factor-β1-induced plasminogen activator inhibitor-1 signaling

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Abstract

Aim: To investigate the effect of microtubule stabilization with low-dose paclitaxel on renal fibrosis, focusing on the transforming growth factor-β1 (TGF-β1)-induced plasminogen activator inhibitor-1 (PAI-1) signaling cascade. Methods: Forty-eight rats were randomly assigned to four groups: sham/vehicle, sham/paclitaxel, unilateral ureteral obstruction (UUO)/vehicle and UUO/paclitaxel. Rats were treated with a 0.3 mg/kg intraperitoneal dose of paclitaxel or vehicle twice per week for 14 days. Half of the rats in each group were sacrificed respectively on day 7 and 14 after operation. Inner medullar collecting duct (IMCD) cells stimulated with TGF-β1 were incubated with 0, 1 and 2 nM paclitaxel for 24 and 72 hours. Histological changes were assessed using periodic acid-Schiff and Masson's trichrome. The TGF-β1-induced PAI-1 signaling and status of extracellular matrix proteins were evaluated by western blot analysis. Results: In the UUO kidneys, paclitaxel significantly attenuated tubular damage and interstitial collagen deposition, as well as α-smooth muscle actin (α-SMA), TGF-β1 and PAI-1 protein expression. Paclitaxel also inhibited the UUO-induced activation of Smad2/3 and c-Jun N-terminal kinase (JNK). However, paclitaxel treatment did not inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) or p38 expression. In TGF-β1-treated IMCD cells, treatment with 1 and 2 nM paclitaxel for 72 h reduced fibronectin, α-SMA and PAI-1 protein expression. Moreover, a 2 nM dose of paclitaxel for 24 h significantly inhibited the TGF-β1-stimulated activation of Smad2/3, JNK and ERK1/2 in IMCD cells. Conclusion: Paclitaxel at low non-cytotoxic doses ameliorates renal fibrosis by inhibiting multiple steps in the TGF-β1-induced PAI-1 signaling including Smads and mitogen-activated protein kinases.

Original languageEnglish
Pages (from-to)574-582
Number of pages9
JournalNephrology
Volume21
Issue number7
DOIs
StatePublished - 1 Jul 2016

Keywords

  • fibrosis
  • mitogen-activated protein kinases
  • paclitaxel
  • plasminogen activator inhibitor-1
  • smad proteins

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