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NDT Advance Access originally published online on February 16, 2009
Nephrology Dialysis Transplantation 2009 24(8):2392-2399; doi:10.1093/ndt/gfp041
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© The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Blocking adenosine A2A receptor reduces peritoneal fibrosis in two independent experimental models

Sigal Nakav1, Leonid Kachko2, Marina Vorobiov3, Boris Rogachev3, Cidio Chaimovitz3, Moshe Zlotnik3 and Amos Douvdevani1,3

1 Department of Clinical Biochemistry 2 Department of Pathology 3 Department of Nephrology, Soroka Medical Center and Ben-Gurion University of the Negev, Beer Sheva, Israel

Correspondence and offprint requests to: Amos Douvdevani; E-mail: amosd{at}bgu.ac.il



  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 A2A receptor (A2AR) 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 A2AR in two experimental models.

Methods. Collagen deposition was evaluated in primary peritoneal fibroblasts following treatment with an A2AR 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 A2AR antagonist) in drinking water or between (A2AR+/+) mice and A2AR-deficient mice (A2AR–/–).

Results. Adenosine or the A2AR agonist CGS21680 stimulated collagen production by peritoneal fibroblasts in vitro and A2AR antagonists (ZM241385 and caffeine) blocked this effect. Consistent with these results, caffeine-treated WT or A2AR–/– 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 A2AR and A2BR mRNA levels induced by CG or PDF while it upregulated A1R levels.

Conclusion. Our data suggest that adenosine through its A2AR promotes peritoneal fibrosis and therefore should be considered as a target for pharmacological intervention.

Keywords: A2A receptor; adenosine; caffeine; peritoneal fibroblasts; peritoneal fibrosis

Received for publication: 19.10.08
Accepted in revised form: 20. 1.09


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