Previous studies have yielded conflicting results as to whether extracellular adenosine generation and signaling contributes to hypoxia-induced increases in renal erythropoietin (EPO) secretion. In this study, we combined pharmacological and genetic approaches to elucidate a potential contribution of extracellular adenosine to renal EPO release in mice. To stimulate EPO secretion, we used murine carbon monoxide exposure (400 and 750 parts per million CO, 4 h), ambient hypoxia (8% oxygen, 4 h), or arterial hemodilution. Because the ecto-5-nucleotidase (CD73, conversion of AMP to adenosine) is considered the pacemaker of extracellular adenosine generation, we first tested the effect of blocking extracellular adenosine generation with the specific CD73-inhibitor adenosine 5'-(α, -methylene) diphosphate (APCP) or by gene-targeted deletion of cd73 . These studies showed that neither APCP-treatment nor targeted deletion of cd73 resulted in changes of stimulated EPO mRNA or serum levels, although the increases of adenosine levels in the kidney following CO exposure were attenuated in mice with APCP treatment or in cd73 –/– mice. Moreover, pharmacological studies using specific inhibitors of individual adenosine receptors (A 1 AR, DPCPX; A 2A AR, DMPX; A 2B AR, PSB 1115; A 3 AR, MRS 1191) showed no effect on stimulated increases of EPO mRNA or serum levels. Finally, stimulated EPO secretion was not attenuated in gene-targeted mice lacking A 1 AR –/– , A 2A AR –/– , A 2B AR –/– , or A 3 AR –/– . Together, these studies combine genetic and pharmacological in vivo evidence that increases of EPO secretion during limited oxygen availability are not affected by extracellular adenosine generation or signaling. adenosine receptors; ecto-5'-nucleotidase; CD73; carbon monoxide Address for reprint requests and other correspondence: H. K. Eltzschig, Mucosal Inflammation Program, Dept. of Anesthesiology and Perioperative Medicine, Univ. of Colorado Health Sciences Center, 4200 E. Ninth Ave., Campus Box B113, Denver, CO 80262 (e-mail: holger.eltzschig@uchsc.edu ) or H. Osswald, Dept. of Pharmacology and Toxicology, Tübingen Univ. Hospital, Wilhelmstr. 56, D-72074 Tübingen, Germany (e-mail: hartmut.osswald@uni-tuebingen.de )
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Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia
Grenz, Almut; Zhang, Hua; Weingart, Jochen; von Wietersheim, Simone; Eckle, Tobias; Schnermann, Juergen; Köhle, Christoph; Kloor, Doris; Gleiter, Christoph H.; Vallon, Volker; Eltzschig, Holger K.; Osswald, Hartmut
Follow AJP - Renal Physiology
, Volume 293 (5): F1501
The American Physiological Society – Nov 1, 2007
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