title: The dipeptide alanyl-glutamine ameliorates peritoneal fibrosis and attenuates IL-17 dependent pathways during peritoneal dialysis.
abstract: Peritoneal dialysis (PD) can result in chronic inflammation and progressive peritoneal membrane damage. Alanyl-Glutamine (Ala-Gln), a dipeptide with immunomodulatory effects, improved resistance of mesothelial cells to PD fluids. Recently, interleukin-17 (IL-17) was found to be associated with PD-induced peritoneal damage. Here we studied the capacity of intraperitoneal Ala-Gln administration to protect against peritoneal damage by modulating IL-17 expression in uremic rat and mouse PD exposure models. Supplementation of PD fluid with Ala-Gln resulted in reduced peritoneal thickness, αSMA expression and angiogenesis. Addition of Ala-Gln also attenuated the IL-17 pathway expression induced by PD, reflected by substantial reduction or normalization of peritoneal levels of IL-17, transforming growth factor β, IL-6, and the transcription factor retinoic acid receptor-related orphan receptor gamma T. Moreover, increased levels of IL-17 were associated with PD-induced peritoneal thickening. Conversely, Ala-Gln treatment prevented peritoneal extracellular matrix deposition, an effect seen with IL-17 blockade. Thus, intraperitoneal administration of Ala-Gln, a stable dipeptide commonly used in parenteral nutrition, ameliorates PD-induced peritoneal damage in animal models, in part by modulating IL-17 expression. Hence, Ala-Gln supplementation of dialysate may be a potential strategy to ameliorate peritoneal deterioration during PD.
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Evelina
authors.initials: E
authors.lastname: Ferrantelli
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
authors.forename: Georgios
authors.initials: G
authors.lastname: Liappas
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Vila Cuenca
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Eelco D
authors.initials: ED
authors.lastname: Keuning
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Foster
authors.affiliation: Department of Nephrology, VU University Medical Center Amsterdam, The Netherlands.
authors.forename: Marc G
authors.initials: MG
authors.lastname: Vervloet
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Lopéz-Cabrera
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: Rhj.beelen@vumc.nl.
authors.forename: Robert H J
authors.initials: RH
authors.lastname: Beelen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019610:Cytoprotection; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D056627:Peritoneal Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010537:Peritoneum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015415:Biomarkers; D004151:Dipeptides; D018836:Inflammation Mediators; D020381:Interleukin-17; D020011:Protective Agents; C054122:alanylglutamine
keywords: Ala-Gln; IL-17; fibrosis; peritoneal dialysis; peritoneal membrane