title: Sorafenib ameliorates renal fibrosis through inhibition of TGF-β-induced epithelial-mesenchymal transition.
abstract: OBJECTIVE
  This study was to investigate whether sorafenib can inhibit the progression of renal fibrosis and to study the possible mechanisms of this effect.
  
  
  METHODS
  Eight-week-old rats were subjected to unilateral ureteral obstruction (UUO) and were intragastrically administered sorafenib, while control and sham groups were administered vehicle for 14 or 21 days. NRK-52E cells were treated with TGF-β1 and sorafenib for 24 or 48 hours. HE and Masson staining were used to visualize fibrosis of the renal tissue in each group. The expression of α-SMA and E-cadherin in kidney tissue and NRK-52E cells were performed using immunohistochemistry and immunofluorescence. The apoptosis rate of NRK-52E cells was determined by flow cytometry analysis. The protein levels of Smad3 and p-Smad3 in kidney tissue and NRK-52E cells were detected by western blot analysis.
  
  
  RESULTS
  HE staining demonstrated that kidney interstitial fibrosis, tubular atrophy, and inflammatory cell infiltration in the sorafenib-treated-UUO groups were significantly decreased compared with the vehicle-treated-UUO group (p<0.05). Masson staining showed that the area of fibrosis was significantly decreased in the sorafenib-treated-UUO groups compared with vehicle-treated-UUO group (p<0.01). The size of the kidney did not significantly increase; the cortex of the kidney was thicker and had a richer blood supply in the middle-dose sorafenib group compared with the vehicle-treated-UUO group (p<0.05). Compared with the vehicle-treated-UUO and TGF-β-stimulated NRK-52E groups, the expression of a-SMA and E-cadherin decreased and increased, respectively, in the UUO kidneys and NRK-52E cells of the sorafenib-treated groups (p<0.05). The apoptotic rate of NRK-52E cells treated with sorafenib decreased for 24 hours in a dose-dependent manner (p<0.05). Compared with the vehicle-treated UUO and TGF-β-stimulated NRK-52E groups, the ratio of p-Smad3 to Smad3 decreased in the sorafenib-treated groups (p<0.05).
  
  
  CONCLUSIONS
  Our results suggest that sorafenib may useful for the treatment of renal fibrosis through the suppression of TGF-β/Smad3-induced EMT signaling.
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Lining
authors: L
authors: Jia
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Xiaotao
authors: X
authors: Ma
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Baosong
authors: B
authors: Gui
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Heng
authors: H
authors: Ge
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Li
authors: L
authors: Wang
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Yan
authors: Y
authors: Ou
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Lifang
authors: L
authors: Tian
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Zhao
authors: Z
authors: Chen
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Zhaoyang
authors: Z
authors: Duan
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Jin
authors: J
authors: Han
authors: Department of Nephropathy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors: Rongguo
authors: R
authors: Fu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005355:Fibrosis; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D051900:Smad3 Protein / Q000378:metabolism; D000077157:Sorafenib; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D000199:Actins; D015820:Cadherins; D009536:Niacinamide; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D051900:Smad3 Protein; D000077157:Sorafenib; D016212:Transforming Growth Factor beta; C498862:Acta2 protein, rat