The dipeptide alanyl-glutamine ameliorates peritoneal fibrosis and attenuates IL-17 dependent pathways during peritoneal dialysis

Kidney Int. 2016 Mar;89(3):625-35. doi: 10.1016/j.kint.2015.12.005. Epub 2016 Jan 8.

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.

Keywords: Ala-Gln; IL-17; fibrosis; peritoneal dialysis; peritoneal membrane.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cytoprotection
  • Dipeptides / pharmacology*
  • Disease Models, Animal
  • Epithelial-Mesenchymal Transition / drug effects
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / pathology
  • Female
  • Inflammation Mediators / metabolism*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic
  • Peritoneal Dialysis / adverse effects*
  • Peritoneal Fibrosis / etiology
  • Peritoneal Fibrosis / metabolism
  • Peritoneal Fibrosis / pathology
  • Peritoneal Fibrosis / prevention & control*
  • Peritoneum / drug effects*
  • Peritoneum / metabolism
  • Peritoneum / pathology
  • Protective Agents / pharmacology*
  • Rats, Wistar
  • Signal Transduction / drug effects

Substances

  • Biomarkers
  • Dipeptides
  • Inflammation Mediators
  • Interleukin-17
  • Protective Agents
  • alanylglutamine