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• W2072860244 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. 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. Renal fibrosis is an inevitable consequence of many chronic kidney diseases. Among the diverse causative factors, transforming growth factor-β1 (TGF-β1) can strongly induce renal fibrosis.1.Border W.A. Noble N.A. TGF-beta in kidney fibrosis: a target for gene therapy.Kidney Int. 1997; 51: 1388-1396Abstract Full Text PDF PubMed Scopus (377) Google Scholar, 2.Bottinger E.P. TGF-beta in renal injury and disease.Semin Nephrol. 2007; 27: 309-320Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 3.Wang W. Koka V. Lan H.Y. Transforming growth factor-beta and Smad signalling in kidney diseases.Nephrology (Carlton). 2005; 10: 48-56Crossref PubMed Scopus (309) Google Scholar TGF-β1 is a multifunctional cytokine that evokes diverse cellular responses,4.Kubiczkova L. Sedlarikova L. Hajek R. et al.TGF-β - an excellent servant but a bad master.J Transl Med. 2012; 10: 183Crossref PubMed Scopus (308) Google Scholar, 5.Prud'homme G.J. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations.Lab Invest. 2007; 87: 1077-1091Crossref PubMed Scopus (312) Google Scholar, 6.Li M.O. Wan Y.Y. Sanjabi S. et al.Transforming growth factor-beta regulation of immune responses.Annu Rev Immunol. 2006; 24: 99-146Crossref PubMed Scopus (1742) Google Scholar, 7.Rubtsov Y.P. Rudensky A.Y. TGFbeta signalling in control of T-cell mediated self- reactivity.Nat Rev Immunol. 2007; 7: 443-453Crossref PubMed Scopus (264) Google Scholar, 8.Böttinger E.P. Letterio J.J. Roberts A.B. Biology of TGF-beta in knockout and transgenic mouse models.Kidney Int. 1997; 51: 1355-1360Abstract Full Text PDF PubMed Scopus (150) Google Scholar, 9.Kulkarni A.B. Karlsson S. Transforming growth factor-beta-1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease.Am J Pathol. 1993; 143: 3-9PubMed Google Scholar including fibrosis, by binding to cell surface receptors.10.Zhou J. Zhong D.W. Wang Q.W. et al.Paclitaxel ameliorates fibrosis in hepatic stellate cells via inhibition of TGF-beta/Smad activity.World J Gastroenterol. 2010; 16: 3330-3334Crossref PubMed Scopus (53) Google Scholar TGF-β superfamily receptors include seven type I receptors (activin receptor-like kinases 1 to 7 (ALK1–7), five type II receptors (TGF-β receptor II (TGF-βRII), activin type II receptor, activin type IIB receptor, bone morphogenetic protein receptor type II, and anti-Müllerian hormone type II receptor), and two type III receptors (Betaglycan and Endoglin) in mammals.11.Liu T. Feng X.H. Regulation of TGF-beta signalling by protein phosphatases.Biochem J. 2010; 430: 191-198Crossref PubMed Scopus (79) Google Scholar,12.O Scherner SK Meurer L Tihaa et al.Endoglin differentially modulates antagonistic transforming growth factor-β1 and BMP-7 signaling.J Biol Chem. 2007; 282: 13934-13943Crossref PubMed Scopus (86) Google Scholar TGF-β1 signals through receptor complexes consisting of type I (TGF-βRIs) and type II receptors (TGF-βRIIs), and the activated receptors phosphorylate and activate the Smad proteins, which form transcriptional complexes that control the expression of a number of target genes with various functions.13.Sato M. Muragaki Y. Saika S. et al.Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.J Clin Invest. 2003; 112: 1486-1494Crossref PubMed Scopus (697) Google Scholar Therefore, we hypothesized that some of the receptors may have important roles during renal fibrosis, and that these receptors might be novel therapeutic targets for renal fibrosis. However, the subtype-specific expression of the diverse range of TGF-β superfamily receptors during renal fibrosis remains to be determined. Currently, inhibition of protein expression is a common strategy to abolish the function of proteins in certain diseases. However, data increasingly indicate that posttranslational modifications mediate direct and definitive regulation of protein function, which can be independent of the protein expression levels in some pathophysiological processes.14.GK Kumar JB Klein Analysis of expression and post-translational modification of proteins during hypoxia.J Appl Physiol. 2004; 96: 1178-1186Crossref PubMed Scopus (12) Google Scholar,15.Hao P. Guo T. Sze S.K. Simultaneous analysis of proteome, phospho- and glycoproteome of rat kidney tissue with electrostatic repulsion hydrophilic interaction chromatography.PLoS One. 2011; 6: 16884Crossref Scopus (51) Google Scholar Therefore, such modifications may be a critical regulator of protein function. Glycosylation is a crucial posttranslational modification that has profound effects on the regulation of various physiological processes, including cell growth, differentiation, and migration,16.Takahashi M. Kuroki Y. Ohtsubo K. et al.Core fucose and bisecting GlcNAc, the direct modifiers of the N-glycan core: their functions and target proteins.Carbohydr Res. 2009; 344: 1387-1390Crossref PubMed Scopus (170) Google Scholar,17.Zhao Y.Y. Takahashi M. Gu J.G. et al.Functional roles of N-glycans in cell signaling and cell adhesion in cancer.Cancer Sci. 2008; 99: 1304-1310Crossref PubMed Scopus (314) Google Scholar all of which are involved in kidney disease. The TGF-β superfamily receptors TGF-βRII and TGF-βRI (ALK5) are both glycoproteins.18.Lin S.J. Lerch T.F. Cook R.W. et al.The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding.Reproduction. 2006; 132: 179-190Crossref PubMed Scopus (115) Google Scholar Our recent study showed that diminishing the core fucosylation of TGF-βRII and ALK5, which is catalyzed by α-1,6 fucosyltransferase (FUT8), blocked renal tubular epithelial–mesenchymal transition in cultured human renal proximal tubular epithelial cells in vitro.19.Lin H. Wang D. Wu T. et al.Blocking the core fucosylation of TGF-β1-receptors down-regulates their functions and attenuates the epithelial mesenchymal transition of renal tubular cells.Am J Physiol Renal Physiol. 2011; 300: 1017-1025Crossref PubMed Scopus (57) Google Scholar However, to date, the blockade of protein function in vivo by inhibiting core fucosylation has not yet been reported in kidney disease. In this study, we screened and identified the TGF-β superfamily receptors that correlated with renal fibrosis induced by unilateral ureteral obstruction (UUO). We observed that TGF-βRII and TGF-βRI (ALK5) were the critical TGF-β1 receptors for this process. We also investigated the role of core fucosylation on the expression and function of these TGF-β1 receptors in vivo during renal fibrosis. Our results suggest that core fucosylation has a crucial role in TGF-β1R function, and the blockade of core fucosylation successfully abolished the activation of TGF-β/Smad signaling and attenuated renal fibrosis induced by UUO. Targeting the posttranslational modifications of key proteins may provide a novel and effective strategy for the treatment of fibrotic renal disorders. To examine the expression levels of the TGF-β superfamily receptors in the UUO kidney, we compared the gene expression profiles of kidneys from the UUO7d and Control groups using an RT2Profiler Array. Among the 23 genes examined, significant differential expression of six genes was detected compared with the control group; in the UUO7d group, ALK5, ALK7, TGF-βRII, Smad2, and Smad3 were significantly upregulated, whereas ALK6 was significantly downregulated. Significant differential expression of the other 17 genes was not detected (Figure 1a). Compared with the Control group, ALK5, ALK7, and TGF-βRII mRNA increased progressively in the UUO group from 3 days after surgery (P<0.05), reaching peak levels at 21 days after surgery (P<0.01). The expression of ALK6 mRNA decreased progressively in the UUO group from 3 days after surgery (P<0.05), reaching the lowest level at 21 days after surgery (P<0.01; Figure 1b). Western blot analysis confirmed these observations at the protein level (Figure 1c and d). We investigated the activation of the TGF-β/Smad2/3 pathway in the UUO kidney by quantifying Smad2/3 phosphorylation. Western blot analysis indicated that Smad2/3 and p-Smad2/3 expression increased progressively in the UUO group, was significantly increased 3 days after surgery (P<0.05), and reached peak levels at 21 days after surgery (P<0.01 vs. Control group; Figure 1c and d). An increasing number of studies indicate that posttranslational modifications crucially regulate protein function, and posttranslational modifications may represent potential targets for the treatment of some diseases. Therefore, we examined the core fucosylation levels in the UUO kidney by fluorescent Lens culinaris agglutinin–fluorescein complex (LCA-FITC). We observed low levels of core fucosylation in the normal kidney; however, these levels markedly and progressively increased following surgery in the UUO group (Figure 2a and b). FUT8 is the unique fucosyltransferase responsible for core fucosylation.20.Ihara H. Ikeda Y. Toma S. et al.Crystal structure of mammalian alpha1,6-fucosyltransferase, FUT8.Glycobiology. 2006; 17: 455-466Crossref PubMed Scopus (100) Google Scholar,21.Imai-Nishiya H. Mori K. Inoue M. et al.Double knockdown of alpha1,6-fucosyltransferase (FUT8) and GDP-mannose 4,6-dehydratase (GMD) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibodies with enhanced ADCC.BMC Biotechnol. 2007; 7: 84Crossref PubMed Scopus (112) Google Scholar To investigate the function of core fucosylation in UUO-induced renal fibrosis, we created a FUT8-knockdown UUO rat model. We constructed a FUT8 short hairpin RNA (shRNA) recombinant adenovirus vector (Ad-FUT8shRNA) and control adenovirus encoding green fluorescent protein (Ad-GFP), amplified and purified these adenoviruses from HEK-293 cells, and performed adenoviral transfection through rat tail vein injection (Figure 3). Exogenous FUT8shRNA was expressed in the kidney 1 day after infection and was maintained at similar levels for 21 days (Figure 4a and b). We investigated the effects of Ad-FUT8shRNA on endogenous FUT8 expression in the UUO kidney. Real-Time reverse transcriptase–PCR (RT–PCR) and western blot analysis (Figure 4c–e) showed that the endogenous FUT8 expression levels obviously increased in the UUO kidney; however, these levels were significantly downregulated at the mRNA and protein levels in both the ShamFUT8shRNA and UUOFUT8shRNA groups. These data indicated successful generation of a FUT8-knockdown UUO rat model. We investigated whether core fucosylation could be reduced by FUT8shRNA in the UUO kidney using rhodamine-labeled Lens culinaris agglutinin (LCA-TRITC). As shown in Figure 5a and b, FUT8shRNA effectively inhibited core fucosylation in the Control group (ControlFUT8shRNA+ rats). FUT8shRNA also prevented an increase in core fucosylation after surgery in the kidney of the UUO FUT8shRNA group as compared with the progressive increase observed after surgery in the UUO group. Our data indicated that TGF-βRII, TGF-βRI (ALK5), ALK6, and ALK7 are the key TGF-β superfamily receptors involved in the renal fibrosis in UUO rats. We hypothesized that targeting of these receptors could provide a possible therapeutic target interference point for renal fibrosis. Recently, we reduced the core fucosylation of TGF-βRII and TGF-βRI (ALK5) in cultured human renal proximal tubular epithelial cells by transient transfection of FUT8shRNA, which successfully reversed the renal tubular epithelial–mesenchymal transition in vitro.19.Lin H. Wang D. Wu T. et al.Blocking the core fucosylation of TGF-β1-receptors down-regulates their functions and attenuates the epithelial mesenchymal transition of renal tubular cells.Am J Physiol Renal Physiol. 2011; 300: 1017-1025Crossref PubMed Scopus (57) Google Scholar Therefore, in this study, we investigated whether TGF-βRII and ALK5 are modified by core fucosylation in the kidney. Core fucose bands were detected after immunoprecipitation with TGF-βRII and ALK5 antibodies, demonstrating that TGF-βRII and ALK5 are modified by core fucosylation (Figure 6a and b). Next, we determined the spatial relationship of core fucose with TGF-βRII and ALK5 using double fluorescent labeling. The expression of core fucose epitopes completely overlapped with that of both TGF-βRII and ALK5 epitopes in a significant number of tubular epithelial cells, confirming that both TGF-βRII and ALK5 are modified by core fucosylation in the UUO kidney (Figure 6c–f). We measured the protein expression levels of TGF-βRII and ALK5, and observed that TGF-βRII and ALK5 were upregulated with increased core fucosylation in UUO kidneys (Figure 6a and b). This effect was markedly suppressed by FUT8shRNA; however, FUT8shRNA had no effect on the expression levels of TGF-βRII and ALK5 (Figure 6a and b). Double fluorescent labeling confirmed that the core fucosylation of TGF-βRII and ALK5 markedly and progressively increased after surgery in the UUO group; however, this effect was prevented by FUT8shRNA (Figure 6c–f). To explore the effects of core fucosylation on the functionality of TGF-βRII and ALK5, we investigated whether inhibiting core fucosylation of TGF-βRII and ALK5 could abolish the activation of the TGF-β/Smad2/3 pathway. Western blot and immunofluorescence analysis indicated that p-Smad2/3 was expressed mostly in tubule epithelium, rather than in the interstitial cells, and the expression increased progressively after surgery in the UUO group; however, the abolition of ALK5 and TGF-βRII core fucosylation using FUT8shRNA effectively suppressed this increase after surgery in the UUOFUT8shRNA group (Figure 7a–d). Extracellular matrix accumulation is critically involved in UUO-induced renal fibrosis. Therefore, we examined extracellular matrix–associated protein markers to determine the effects of reduced TGF-βRII and ALK5 core fucosylation on renal fibrosis. Western blot analysis demonstrated that the expression of extracellular matrix proteins (collagen I, collagen III, fibronectin, and tissue inhibitor of metalloproteinase 1 (TIMP-1)) were markedly elevated after surgery in the UUO group, consistent with an increase in core fucose staining. Transfection of FUT8shRNA markedly prevented UUO-induced changes in extracellular matrix protein expression (Figure 8a and b). Furthermore, inhibition of core fucosylation using FUT8shRNA reversed UUO-induced expression of the inflammatory cytokine monocyte chemoattractant protein-1 (MCP-1; Figure 8c and d). Finally, we examined the effects of FUT8shRNA on pathological changes in the renal interstitium and tubules in paraffin-embedded tissue sections using periodic acid–Schiff, periodic acid–Schiff-methenamine silver, and Masson’s trichrome staining. On day 7 after UUO, the kidneys of untreated rats (FUT8shRNA-) were characterized by widespread renal tubulointerstitial damage and fibrosis. In comparison, FUT8shRNA+ rats exhibited markedly decreased tubulointerstitial damage and fibrosis at 7 days after UUO, and these differences were more evident at day 14 after UUO (Figure 9a and b). This study has provided novel insights into the pathogenesis of renal fibrosis in obstructive nephropathy by probing the role of the posttranslational modification, core fucosylation, in kidney disease for the first time. We found that core fucose was expressed at low levels in the normal rat kidney, and markedly increased in rat UUO kidneys, which was closely associated with the overexpression of extracellular matrix components, including collagen I, collagen III, fibronectin, and TIMP-1. In addition, we demonstrated that core fucosylation of ALK5 and TGF-βRII was essential for their function and subsequent activation of TGF-β/Smad signaling. Furthermore, the downregulation of core fucosylation by transfection of Ad-FUT8shRNA inhibited extracellular matrix molecule overexpression and ameliorated renal fibrosis in UUO rats because of the inactivation of the TGF-β/Smad pathway. Our findings further elucidate the mechanisms of renal fibrosis and suggest that core fucosylation may be exploited as a novel therapeutic target for the treatment of renal fibrosis. TGF-β1 has long been considered to be a key mediator of renal fibrosis in both experimental and human kidney disease.1.Border W.A. Noble N.A. TGF-beta in kidney fibrosis: a target for gene therapy.Kidney Int. 1997; 51: 1388-1396Abstract Full Text PDF PubMed Scopus (377) Google Scholar, 2.Bottinger E.P. TGF-beta in renal injury and disease.Semin Nephrol. 2007; 27: 309-320Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, 3.Wang W. Koka V. Lan H.Y. Transforming growth factor-beta and Smad signalling in kidney diseases.Nephrology (Carlton). 2005; 10: 48-56Crossref PubMed Scopus (309) Google Scholar TGF-β1 is a highly pleiotropic cytokine4.Kubiczkova L. Sedlarikova L. Hajek R. et al.TGF-β - an excellent servant but a bad master.J Transl Med. 2012; 10: 183Crossref PubMed Scopus (308) Google Scholar, 5.Prud'homme G.J. Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations.Lab Invest. 2007; 87: 1077-1091Crossref PubMed Scopus (312) Google Scholar, 6.Li M.O. Wan Y.Y. Sanjabi S. et al.Transforming growth factor-beta regulation of immune responses.Annu Rev Immunol. 2006; 24: 99-146Crossref PubMed Scopus (1742) Google Scholar that exerts a broad range of anti-inflammatory and immunosuppressive effects.6.Li M.O. Wan Y.Y. Sanjabi S. et al.Transforming growth factor-beta regulation of immune responses.Annu Rev Immunol. 2006; 24: 99-146Crossref PubMed Scopus (1742) Google Scholar,7.Rubtsov Y.P. Rudensky A.Y. TGFbeta signalling in control of T-cell mediated self- reactivity.Nat Rev Immunol. 2007; 7: 443-453Crossref PubMed Scopus (264) Google Scholar Knockout of TGF-β1 in mice results in autoimmunity and early death due to multiorgan inflammatory disease.8.Böttinger E.P. Letterio J.J. Roberts A.B. Biology of TGF-beta in knockout and transgenic mouse models.Kidney Int. 1997; 51: 1355-1360Abstract Full Text PDF PubMed Scopus (150) Google Scholar,9.Kulkarni A.B. Karlsson S. Transforming growth factor-beta-1 knockout mice. A mutation in one cytokine gene causes a dramatic inflammatory disease.Am J Pathol. 1993; 143: 3-9PubMed Google Scholar In this study, we confirmed that the expression of ALK5, ALK7, and TGF-βRII increased during the progression of renal fibrosis induced by UUO, whereas ALK6 decreased (Figure 1). This result indicates that the activation of TGF-β and activin signaling and interference with bone morphogenetic protein signaling may occur during renal fibrosis in UUO kidneys. Several studies have previously demonstrated that the diversity of TGF-β1 functions relies on its different receptors.22.Piek E. Heldin C.H. Ten Dijke P. Specificity, diversity, and regulation in TGF-beta superfamily signaling.FASEB J. 1999; 13: 2105-2124Crossref PubMed Scopus (741) Google Scholar,23.Meng X.M. Huang X.R. Xiao J. et al.Diverse roles of TGF-β receptor II in renal fibrosis and inflammation in vivo and in vitro.J Pathol. 2012; 227: 175-188Crossref PubMed Scopus (116) Google Scholar Recently, aberrant protein glycosylation, rather than altered protein expression levels, has been associated with tumor development.24.Pinho S.S. Osorio H. Nita-Lazar M. et al.Role of E-cadherin N-glycosylation profile in a mammary tumor model.Biochem Biophs Res Commun. 2009; 379: 1091-1096Crossref PubMed Scopus (69) Google Scholar For example, α-fetoprotein (AFP) is a well-known glycoprotein that is commonly used to detect hepatocellular carcinoma. The increased expression of AFP provides limited clinical information and is only suggestive of prognosis in hepatocellular carcinoma because of low specificity (∼50%); however, the aberrantly glycosylated AFP-L3 isoform is particularly useful for the early identification of aggressive hepatocellular carcinoma, with a specificity of 96%.25.Aoyagi Y. Suzuk Y. Isemura M. et al.The fucosylation index of alpha-fetoprotein and its usefulness in the early diagnosis of hepatocellular carcinoma.Cancer. 1988; 61: 769-774Crossref PubMed Scopus (159) Google Scholar Interestingly, the majority of the US Food and Drug Administration–approved cancer biomarkers are glycoproteins, including AFP, prostate cancer antigen, carcinoembryonic antigen, and Her-2/neu,26.Kim Y.S. Yoo H.S. Ko J.H. Implication of aberrant glycosylation in cancer and use of lectin for cancer biomarker discovery.Protein Pept Lett. 2009; 16: 499-507Crossref PubMed Scopus (34) Google Scholar and posttranslational glycosylation is becoming an important, attractive biomarker and a treatment target in cancer.27.Goldman R. Ressom H.W. Varghese R.S. et al.Detection of hepatocellular carcinoma using glycomic analysis.Clin Cancer Res. 2009; 15: 1808-1813Crossref PubMed Scopus (121) Google Scholar, 28.Kondo A. Identification of target proteins of glycosyltransferases using functional glycomics by gene expression regulation.Trends Glycosci Glycotechnol. 2007; 19: 247-256Crossref Scopus (3) Google Scholar, 29.Jin H. Zangar R.C. Protein modifications as potential biomarkers in breast cancer.Biomark Insights. 2009; 4: 191-200PubMed Google Scholar, 30.Matsumoto K. Shimizu C. Arao T. et al.Identification of predictive biomarkers for response to trastuzumab using plasma FUCA activity and N-glycan identified by MALDI-TOF-MS.J Proteome Res. 2009; 8: 457-462Crossref PubMed Scopus (20) Google Scholar Increased expression of fucosyltransferases is found in various tumor cells and has been correlated with aspects of tumor progression such as metastasis and cell adhesion. Thus, fucosyltransferase inhibitors are potentially useful as antitumor agents.31.Lin T.W. Chang W.W. Chen C.C. et al.Stachybotrydial, a potent inhibitor of fucosyltransferase and sialyltransferase.Biochem Biophys Res Commun. 2005; 331: 953-957Crossref PubMed Scopus (27) Google Scholar In contrast to studies in cancer, studies on the posttranslational glycosylation of proteins in kidney disease are almost nonexistent. In fact, the diverse range of glycan structures has specific functions in eukaryotic cells. Altered cellular glycosylation is associated with increased cell proliferation, migration, and apoptosis,16.Takahashi M. Kuroki Y. Ohtsubo K. et al.Core fucose and bisecting GlcNAc, the direct modifiers of the N-glycan core: their functions and target proteins.Carbohydr Res. 2009; 344: 1387-1390Crossref PubMed Scopus (170) Google Scholar, 17.Zhao Y.Y. Takahashi M. Gu J.G. et al.Functional roles of N-glycans in cell signaling and cell adhesion in cancer.Cancer Sci. 2008; 99: 1304-1310Crossref PubMed Scopus (314) Google Scholar, 32.Ohtsubo K. Marth J.D. Glycosylation in cellular mechanisms of health and disease.Cell. 2006; 126: 855-867Abstract Full Text Full Text PDF PubMed Scopus (2076) Google Scholar all of which are involved in kidney disease. Our previous studies confirmed that blocking the core fucosylation of TGF-βRII and ALK5, a major mechanism of glycosylation, inactivated TGF-β/Smad2/3 signaling and reversed the renal tubular epithelial–mesenchymal transition in cultured human renal proximal tubular epithelial cells in vitro.19.Lin H. Wang D. Wu T. et al.Blocking the core fucosylation of TGF-β1-receptors down-regulates their functions and attenuates the epithelial mesenchymal transition of renal tubular cells.Am J Physiol Renal Physiol. 2011; 300: 1017-1025Crossref PubMed Scopus (57) Google Scholar In this study, we investigated the role of TGF-βRII and ALK5 core fucosylation in vivo. We used a UUO fibrosis model, in which TGF-β/Smad2/3 signaling is the key profibrotic pathway. We found that core fucose was present at low levels in the renal epithelial cells of the normal rat kidney and was elevated significantly in the UUO kidney (Figure 2). We also observed that the level of core fucosylation increased with the levels of TGF-β receptors (Figure 1b–d), suggesting that core fucosylation may have a pathological role in renal fibrosis. Wang et al.33.Wang X. Inoue S. Gu J. et al.Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice.Proc Natl Acad Sci USA. 2005; 102: 15791-15796Crossref PubMed Scopus (347) Google Scholar demonstrated that TGF-βRII was regulated by core fucosylation, which was dependent on FUT8, a fucosyltransferase that specifically catalyzes the introduction of fucose to position 6 of the initial N-acetyl glucosamine residue of the N-glycan core to produce ‘core fucose.’20.Ihara H. Ikeda Y. Toma S. et al.Crystal structure of mammalian alpha1,6-fucosyltransferase, FUT8.Glycobiology. 2006; 17: 455-466Crossref PubMed Scopus (100) Google Scholar,21.Imai-Nishiya H. Mori K. Inoue M. et al.Double knockdown of alpha1,6-fucosyltransferase (FUT8) and GDP-mannose 4,6-dehydratase (GMD) in antibody-producing cells: a new strategy for generating fully non-fucosylated therapeutic antibodies with enhanced ADCC.BMC Biotechnol. 2007; 7: 84Crossref PubMed Scopus (112) Google Scholar Wang et al.33.Wang X. Inoue S. Gu J. et al.Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice.Proc Natl Acad Sci USA. 2005; 102: 15791-15796Crossref PubMed Scopus (347) Google Scholar showed that FUT8-knockout mice induced severe growth retardation, early death during postnatal development, and emphysema-like changes in the lung due to the absence of core fucosylation of TGF-βRII.34.Wang X. Gu J. Miyoshi E. et al.Phenotype changes of Fut8 knockout mouse: core fucosylation is crucial for the function of growth factor receptor(s).Methods Enzymol. 2006; 417: 11-22Crossref PubMed Scopus (63) Google Scholar To further elucidate the role of core fucosylation in the UUO kidney, we designed, synthesized, and fluorescently labeled a FUT8shRNA adenovirus (Figure 3) FUT8shRNA, which was expressed continually for 21 days in adenovirus-infected rats (Figure 4a and b), resulting in marked knockdown of endogenous FUT8 expression (Figure 4c–e) and leading to the inhibition of core fucosylation in the UUO kidney (Figure 5). In accordance with previous research,13.Sato M. Muragaki Y. Saika S. et al.Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.J Clin Invest. 2003; 112: 1486-1494Crossref PubMed Scopus (697) Google Scholar, 19.Lin H. Wang D. Wu T. et al.Blocking the core fucosylation of TGF-β1-receptors down-regulates their functions and attenuates the epithelial mesenchymal transition of renal tubular cells.Am J Physiol Renal Physiol. 2011; 300: 1017-1025Crossref PubMed Scopus (57) Google Scholar, 35.Hong S.W. Isono M. Chen S. et al.Increased glomerular and tubular expression of transforming growth factor-β1, its type II receptor, and activation of the Smad signaling pathway in the db/db mouse.Am J Pathol. 2001; 158: 1653-1663Abstract Full Text Full Text PDF PubMed Google Scholar this study confirmed that TGF-βRII and ALK5 are critical receptors for the profibrotic function of TGF-β1. Both TGF-βRII and ALK5 were modified by core fucosylation in the kid" @default.
• W2072860244 created "2016-06-24" @default.
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• W2072860244 date "2013-07-01" @default.
• W2072860244 modified "2023-10-10" @default.
• W2072860244 title "Inhibition of TGF-β1-receptor posttranslational core fucosylation attenuates rat renal interstitial fibrosis" @default.
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