title: Antifibrotic effects of KS370G, a caffeamide derivative, in renal ischemia-reperfusion injured mice and renal tubular epithelial cells.
abstract: Accumulating evidence suggests that renal tubulointerstitial fibrosis is a main cause of end-stage renal disease. Clinically, there are no beneficial treatments that can effectively reverse the progressive loss of renal functions. Caffeic acid phenethyl ester is a natural phenolic antifibrotic agent, but rapid decomposition by an esterase leads to its low bioavailability. In this study, we evaluated the effects of KS370G, a caffeic acid phenylethyl amide, on murine renal fibrosis induced by unilateral renal ischemia-reperfusion injury (IRI) and in TGF-β₁ stimulated renal tubular epithelial cells (NRK52E and HK-2). In the animal model, renal fibrosis was evaluated at 14 days post-operation. Immediately following the operation, KS370G (10 mg/kg) was administered by oral gavage once a day. Our results show that KS370G markedly attenuates collagen deposition and inhibits an IRI-induced increase of fibronectin, vimentin, α-SMA and TGF-β₁ expression and plasma TGF-β₁ levels in the mouse kidney. Furthermore, KS370G reverses TGF-β1-induced downregulation of E-cadherin and upregulation of α-SMA and also decreases the expression of fibronectin, collagen I and PAI-1 and inhibits TGF-β₁-induced phosphorylation of Smad2/3. These findings show the beneficial effects of KS370G on renal fibrosis in vivo and in vitro with the possible mechanism being the inhibition of the Smad2/3 signaling pathway.
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Sung-Ting
authors: ST
authors: Chuang
authors: 1] Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan [2] Department of Biotechnology, Asia University, Taichung 41354, Taiwan.
authors: Yueh-Hsiung
authors: YH
authors: Kuo
authors: Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
authors: Ming-Jai
authors: MJ
authors: Su
mesh_terms: D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D064200:Cdh1 Proteins / Q000378:metabolism; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000378:metabolism; D007684:Kidney Tubules / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D008297:Male; D008813:Mice, Inbred ICR; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D058258:Serpin E2 / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
chemical_list: D002109:Caffeic Acids; D064200:Cdh1 Proteins; D005353:Fibronectins; C577585:Fzr1 protein, mouse; C554967:KS370G; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D003094:Collagen