Fariba Poosti, Mohammad Ayodhia Soebadi, Helena Crijns, Alexandra De Zutter, Mieke Metzemaekers, Nele Berghmans, Vincent Vanheule, Maarten Albersen, Ghislain Opdenakker, Jo Van Damme, Ben Sprangers, Paul Proost, Sofie Struyf
{"title":"人cxcl9衍生糖胺聚糖结合肽对肾纤维化的抑制作用","authors":"Fariba Poosti, Mohammad Ayodhia Soebadi, Helena Crijns, Alexandra De Zutter, Mieke Metzemaekers, Nele Berghmans, Vincent Vanheule, Maarten Albersen, Ghislain Opdenakker, Jo Van Damme, Ben Sprangers, Paul Proost, Sofie Struyf","doi":"10.1002/cti2.1370","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objectives</h3>\n \n <p>Renal fibrosis accompanies all chronic kidney disorders, ultimately leading to end-stage kidney disease and the need for dialysis or even renal replacement. As such, renal fibrosis poses a major threat to global health and the search for effective therapeutic strategies to prevent or treat fibrosis is highly needed. We evaluated the applicability of a highly positively charged human peptide derived from the COOH-terminal domain of the chemokine CXCL9, namely CXCL9(74–103), for therapeutic intervention. Because of its high density of net positive charges at physiological pH, CXCL9(74–103) competes with full-length chemokines for glycosaminoglycan (GAG) binding. Consequently, CXCL9(74–103) prevents recruitment of inflammatory leucocytes to sites of inflammation.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>CXCL9(74–103) was chemically synthesised and tested <i>in vitro</i> for anti-fibrotic properties on human fibroblasts and <i>in vivo</i> in the unilateral ureteral obstruction (UUO) mouse model.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>CXCL9(74–103) significantly reduced the mRNA and/or protein expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and collagen III by transforming growth factor (TGF)-β1-stimulated human fibroblasts. In addition, administration of CXCL9(74–103) inhibited fibroblast migration towards platelet-derived growth factor (PDGF), without affecting cell viability. In the UUO model, CXCL9(74–103) treatment significantly decreased renal α-SMA, vimentin, and fibronectin mRNA and protein expression. Compared with vehicle, CXCL9(74–103) attenuated mRNA expression of TGF-β1 and the inflammatory markers/mediators MMP-9, F4/80, CCL2, IL-6 and TNF-α. Finally, CXCL9(74–103) treatment resulted in reduced influx of leucocytes in the UUO model and preserved tubular morphology. The anti-fibrotic and anti-inflammatory effects of CXCL9(74–103) were mediated by competition with chemokines and growth factors for GAG binding.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our findings provide a scientific rationale for targeting GAG–protein interactions in renal fibrotic disease.</p>\n </section>\n </div>","PeriodicalId":152,"journal":{"name":"Clinical & Translational Immunology","volume":"11 2","pages":""},"PeriodicalIF":4.6000,"publicationDate":"2022-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cti2.1370","citationCount":"2","resultStr":"{\"title\":\"Inhibition of renal fibrosis with a human CXCL9-derived glycosaminoglycan-binding peptide\",\"authors\":\"Fariba Poosti, Mohammad Ayodhia Soebadi, Helena Crijns, Alexandra De Zutter, Mieke Metzemaekers, Nele Berghmans, Vincent Vanheule, Maarten Albersen, Ghislain Opdenakker, Jo Van Damme, Ben Sprangers, Paul Proost, Sofie Struyf\",\"doi\":\"10.1002/cti2.1370\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objectives</h3>\\n \\n <p>Renal fibrosis accompanies all chronic kidney disorders, ultimately leading to end-stage kidney disease and the need for dialysis or even renal replacement. As such, renal fibrosis poses a major threat to global health and the search for effective therapeutic strategies to prevent or treat fibrosis is highly needed. We evaluated the applicability of a highly positively charged human peptide derived from the COOH-terminal domain of the chemokine CXCL9, namely CXCL9(74–103), for therapeutic intervention. Because of its high density of net positive charges at physiological pH, CXCL9(74–103) competes with full-length chemokines for glycosaminoglycan (GAG) binding. Consequently, CXCL9(74–103) prevents recruitment of inflammatory leucocytes to sites of inflammation.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>CXCL9(74–103) was chemically synthesised and tested <i>in vitro</i> for anti-fibrotic properties on human fibroblasts and <i>in vivo</i> in the unilateral ureteral obstruction (UUO) mouse model.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>CXCL9(74–103) significantly reduced the mRNA and/or protein expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and collagen III by transforming growth factor (TGF)-β1-stimulated human fibroblasts. In addition, administration of CXCL9(74–103) inhibited fibroblast migration towards platelet-derived growth factor (PDGF), without affecting cell viability. In the UUO model, CXCL9(74–103) treatment significantly decreased renal α-SMA, vimentin, and fibronectin mRNA and protein expression. Compared with vehicle, CXCL9(74–103) attenuated mRNA expression of TGF-β1 and the inflammatory markers/mediators MMP-9, F4/80, CCL2, IL-6 and TNF-α. Finally, CXCL9(74–103) treatment resulted in reduced influx of leucocytes in the UUO model and preserved tubular morphology. 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Inhibition of renal fibrosis with a human CXCL9-derived glycosaminoglycan-binding peptide
Objectives
Renal fibrosis accompanies all chronic kidney disorders, ultimately leading to end-stage kidney disease and the need for dialysis or even renal replacement. As such, renal fibrosis poses a major threat to global health and the search for effective therapeutic strategies to prevent or treat fibrosis is highly needed. We evaluated the applicability of a highly positively charged human peptide derived from the COOH-terminal domain of the chemokine CXCL9, namely CXCL9(74–103), for therapeutic intervention. Because of its high density of net positive charges at physiological pH, CXCL9(74–103) competes with full-length chemokines for glycosaminoglycan (GAG) binding. Consequently, CXCL9(74–103) prevents recruitment of inflammatory leucocytes to sites of inflammation.
Methods
CXCL9(74–103) was chemically synthesised and tested in vitro for anti-fibrotic properties on human fibroblasts and in vivo in the unilateral ureteral obstruction (UUO) mouse model.
Results
CXCL9(74–103) significantly reduced the mRNA and/or protein expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and collagen III by transforming growth factor (TGF)-β1-stimulated human fibroblasts. In addition, administration of CXCL9(74–103) inhibited fibroblast migration towards platelet-derived growth factor (PDGF), without affecting cell viability. In the UUO model, CXCL9(74–103) treatment significantly decreased renal α-SMA, vimentin, and fibronectin mRNA and protein expression. Compared with vehicle, CXCL9(74–103) attenuated mRNA expression of TGF-β1 and the inflammatory markers/mediators MMP-9, F4/80, CCL2, IL-6 and TNF-α. Finally, CXCL9(74–103) treatment resulted in reduced influx of leucocytes in the UUO model and preserved tubular morphology. The anti-fibrotic and anti-inflammatory effects of CXCL9(74–103) were mediated by competition with chemokines and growth factors for GAG binding.
Conclusions
Our findings provide a scientific rationale for targeting GAG–protein interactions in renal fibrotic disease.
期刊介绍：
Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.
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