title: Resveratrol inhibits epithelial-mesenchymal transition and renal fibrosis by antagonizing the hedgehog signaling pathway.
abstract: Epithelial-to-mesenchymal transition (EMT), a biologic process in which tubular cells lose their epithelial phenotypes and acquire new characteristic features of mesenchymal properties, is increasingly recognized as an integral part of renal tissue fibrogenesis. Recent studies indicate that resveratrol, a botanical compound derived mainly from the skins of red grapes, may have anti-fibrotic effects in many tissues, but the potential molecular mechanism remains unknown. In the present study, we identified that resveratrol inhibits the induction of EMT and deposition of extracellular matrix (ECM) through antagonizing the hedgehog pathway in vitro and in vivo. In rats with unilateral ureteral obstruction (UUO), administration of resveratrol (20mg/kg/day) significantly reduced serum creatinine. Resveratrol also decreased expression of TGF-β1, and inhibited the phenotypic transition from epithelial cells to mesenchymal cells, and the deposition of ECM in UUO rats. In cultured renal tubular epithelial cells (NRK-52E), TGF-β1-induced EMT and ECM synthesis was abolished with the treatment of resveratrol. The induction of EMT was associated with the activation of the hedgehog pathway. Resveratrol treatment markedly inhibited the over-activity of the hedgehog pathway in the obstructed kidney and in TGF-β1-treated NRK-52E cells, resulted in reduction of cellular proliferation, EMT and ECM accumulation. Thus, these results suggest that resveratrol is able to inhibit EMT and fibrosis in vivo and in vitro through antagonizing the hedgehog pathway, and resveratrol may have therapeutic potential for patients with fibrotic kidney diseases.
authors.affiliation: Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Yongheng
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Transplantation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Cunzao
authors.initials: C
authors.lastname: Wu
authors.affiliation: Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Silu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Lin
authors.affiliation: Wenzhou Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
authors.forename: Bicheng
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Transplantation, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Electronic address: yiningbai@163.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
mesh_terms: D000818:Animals; D002460:Cell Line / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects; D008297:Male; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D013267:Stilbenes / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000503:physiopathology
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C546888:Shh protein, rat; C498555:Smo protein, rat; D000072086:Smoothened Receptor; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; D000077185:Resveratrol
keywords: Epithelial-to-mesenchymal transition (EMT); Hedgehog signaling pathway; Renal fibrosis; Resveratrol