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Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia

¹Department of Pharmacology and Toxicology, Tübingen University Hospital, Tübingen; ²University of Applied Sciences, Albstadt-Sigmaringen; ³Department of Anesthesiology and Intensive Care Medicine, Tübingen University Hospital, Tübingen, Germany; ⁴National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; ⁵Departments of Medicine and Pharmacology, University of California, San Diego, and Veterans Affairs San Diego Healthcare System, San Diego, California; and ⁶Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 24 May 2007 ; accepted in final form 5 September 2007

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'-(,-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 (A₁AR, DPCPX; A_2AAR, DMPX; A_2BAR, PSB 1115; A₃AR, 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 A₁AR^–/–, A_2AAR^–/–, A_2BAR^–/–, or A₃AR^–/–. 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