Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2014
Tamoxifen ameliorates renal tubulointerstitial fibrosis by modulation of estrogen receptor α-mediated transforming growth factor-β1/Smad signaling pathway.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Kim Dal, Lee Ae Sin, Jung Yu Jin, Yang Kyoung Hee, Lee Sik, Park Sung Kwang, Kim Won, Kang Kyung Pyo
Аннотация
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.
CONCLUSION: 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.
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.
CONCLUSION: 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.