title: Blocking adenosine A2A receptor reduces peritoneal fibrosis in two independent experimental models.
abstract: BACKGROUND
  Long-term peritoneal dialysis (PD) is associated with peritoneal fibrosis and loss of function. It has been shown that activation of the adenosine A(2A) receptor (A(2A)R) promotes tissue repair, wound healing and extracellular matrix (ECM) production. We have previously shown that adenosine is a potent regulator of inflammation in the peritoneum. In the current study, we explored the role of adenosine and the A(2A)R in two experimental models.
  
  
  METHODS
  Collagen deposition was evaluated in primary peritoneal fibroblasts following treatment with an A(2A)R agonist and antagonist. In addition, peritoneal fibrosis was induced by i.p. injection of either chlorhexidine gluconate for 2 weeks or 4.25% glucose peritoneal dialysis fluid (PDF) for 1 month. The development of fibrosis was compared between wild-type (WT) and WT mice treated with caffeine (an A(2A)R antagonist) in drinking water or between (A(2A)R(+/+)) mice and A(2A)R-deficient mice (A(2A)R(-/-)).
  
  
  RESULTS
  Adenosine or the A(2A)R agonist CGS21680 stimulated collagen production by peritoneal fibroblasts in vitro and A(2A)R antagonists (ZM241385 and caffeine) blocked this effect. Consistent with these results, caffeine-treated WT or A(2A)R(-/-) mice had reduced submesothelial thickness, collagen deposition and mRNA levels of fibroblast-specific protein (FSP-1) and connective tissue growth factor (CTGF). In addition, treatment with caffeine in vitro and in vivo diminished A(2A)R and A(2B)R mRNA levels induced by CG or PDF while it upregulated A(1)R levels.
  
  
  CONCLUSIONS
  Our data suggest that adenosine through its A(2A)R promotes peritoneal fibrosis and therefore should be considered as a target for pharmacological intervention.
authors.affiliation: Department of Clinical Biochemistry, Soroka Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Nakav
authors.forename: Leonid
authors.initials: L
authors.lastname: Kachko
authors.forename: Marina
authors.initials: M
authors.lastname: Vorobiov
authors.forename: Boris
authors.initials: B
authors.lastname: Rogachev
authors.forename: Cidio
authors.initials: C
authors.lastname: Chaimovitz
authors.forename: Moshe
authors.initials: M
authors.lastname: Zlotnik
authors.forename: Amos
authors.initials: A
authors.lastname: Douvdevani
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002710:Chlorhexidine / Q000031:analogs & derivatives / Q000633:toxicity; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D010529:Peritoneal Cavity / Q000473:pathology*; D010627:Phenethylamines / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D010627:Phenethylamines; D014665:Vasodilator Agents; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D002110:Caffeine; D003094:Collagen; D000241:Adenosine; C010882:chlorhexidine gluconate; D002710:Chlorhexidine