title: Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor α-mediated transforming growth factor-β1/Smad signaling pathway.
abstract: BACKGROUND
  After insult to the kidney, a renal fibrotic process is initiated with sustained inflammation, fibroblast activation and accumulation of extracellular matrix (ECM). Tamoxifen has been used as an anti-estrogen for the prevention and treatment of breast cancer. In this study, we investigated the protective effects of tamoxifen on unilateral ureteral obstruction (UUO)-induced renal tubulointerstitial fibrosis and its molecular mechanism.
  
  
  METHODS
  Renal fibrosis was induced by UUO in 7-week-old C57BL/6 mice. Tamoxifen (50 mg/kg) was given by oral gavage for 5 days before induction of renal fibrosis. Tamoxifen treatment was continued for 14 days after UUO operation. Histologic changes were examined by periodic acid-Schiff stain and Masson's trichrome stain. Expression of α-smooth muscle actin, vimentin, type I collagen, fibronectin and cell adhesion molecules were evaluated by immunohistochemistry and western blot analysis. We also evaluated the effect of tamoxifen on estrogen receptor (ER)-α-mediated transforming growth factor (TGF)-β1/Smad signaling pathway in vitro.
  
  
  RESULTS
  Renal tubular injury and fibrosis were increased after UUO. Tamoxifen treatment significantly decreased UUO-induced renal tubular injury and fibrosis. Renal fibroblast activation, ECM deposition and inflammation were significantly increased after ureteral ligation. However, tamoxifen treatment significantly decreased UUO-induced renal fibroblast activation, ECM deposition and inflammation by suppression of TGF-β1/Smad signaling pathway in vivo. Tamoxifen decreased TGF-β1-induced fibroblast proliferation and cell migration by modulating ERα-mediated TGF-β1/Smad signaling pathway in vitro.
  
  
  CONCLUSIONS
  These findings indicate that tamoxifen has a beneficial effect on UUO-induced tubulointerstitial fibrosis by suppression of renal fibroblast activation via modulation of ERα-mediated renal TGF-β1/Smad signaling pathway.
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Dal
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Ae Sin
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Jung
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Kyoung Hee
authors.initials: KH
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sik
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Sung Kwang
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Won
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Jeonju, Republic of Korea.
authors.forename: Kyung Pyo
authors.initials: KP
authors.lastname: Kang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen
keywords: estrogen receptor-α; fibroblast; inflammation; kidney fibrosis; transforming growth factor-β