title: Low-dose paclitaxel ameliorates renal fibrosis by suppressing transforming growth factor-β1-induced plasminogen activator inhibitor-1 signaling.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors: Eun Sook
authors: ES
authors: Jung
authors: Department of Internal Medicine, Hallym University Hangang Sacred Heart Hospital, Seoul, Korea.
authors: Jeonghwan
authors: J
authors: Lee
authors: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors: Nam Ju
authors: NJ
authors: Heo
authors: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors: Sejoong
authors: S
authors: Kim
authors: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors: Dong Ki
authors: DK
authors: Kim
authors: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors: Kwon Wook
authors: KW
authors: Joo
authors: Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea.
authors: Jin Suk
authors: JS
authors: Han
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D050257:Tubulin Modulators / Q000008:administration & dosage*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D016326:Extracellular Matrix Proteins; D017395:Plasminogen Activator Inhibitor 1; C547314:Serpine1 protein, rat; D051899:Smad2 Protein; C497784:Smad2 protein, rat; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D050257:Tubulin Modulators; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel
keywords: fibrosis; mitogen-activated protein kinases; paclitaxel; plasminogen activator inhibitor-1; smad proteins