Blocking adenosine A2A receptor reduces peritoneal fibrosis in two independent experimental models.
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.
Nakav
Sigal
S
Department of Clinical Biochemistry, Soroka Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel.
Kachko
Leonid
L
Vorobiov
Marina
M
Rogachev
Boris
B
Chaimovitz
Cidio
C
Zlotnik
Moshe
M
Douvdevani
Amos
A
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
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