title: Inhibition of TGF-β1-receptor posttranslational core fucosylation attenuates rat renal interstitial fibrosis.
abstract: The profibrotic cytokine transforming growth factor-β1 (TGF-β1) causes renal fibrosis by binding to receptors at the cell surface; however, it is not clear which of the TGF-β superfamily receptors correlates with renal fibrosis. To resolve this, we quantified TGF-β superfamily receptor expression in the kidneys of rats with unilateral ureteral obstruction using a real-time PCR gene array. Expression of activin receptor-like kinase (ALK)-5, ALK7, and TGF-β receptor II (TGF-βRII) mRNA increased significantly, while ALK6 mRNA expression was significantly decreased in the obstructed rat kidney. Core fucosylation is essential for the proper function of both TGF-βRII and ALK5 in cultured human renal proximal tubular epithelial cells in vitro. Therefore, we targeted posttranslational core fucosylation, regulated by α-1,6 fucosyltransferase (FUT8), by adenoviral-mediated knockdown of FUT8 mRNA in vivo and measured TGF-βRII and ALK5 expression and the progression of renal fibrosis. Despite long-term obstruction injury, inhibition of TGF-βRII and ALK5 of core fucosylation ameliorated the progression of renal fibrosis, an effect independent of TGF-βRII and ALK5 expression. Thus, the regulation of TGF-β1-receptor core fucosylation may provide a novel potential therapeutic strategy for treating renal fibrosis.
authors.affiliation: Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Hongli
authors.initials: H
authors.lastname: Lin
authors.forename: Taihua
authors.initials: T
authors.lastname: Wu
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Xie
authors.forename: Jianing
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhe
authors.initials: Z
authors.lastname: Feng
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D005643:Fucose / Q000378:metabolism*; D005647:Fucosyltransferases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000150:complications
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; C486044:Acvr1c protein, rat; C498216:Bmpr1b protein, rat; D052005:Bone Morphogenetic Protein Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625843:Tgfbr1 protein, rat