title: Role of 2',3'-cyclic nucleotide 3'-phosphodiesterase in the renal 2',3'-cAMP-adenosine pathway.
abstract: Energy depletion increases the renal production of 2',3'-cAMP (a positional isomer of 3',5'-cAMP that opens mitochondrial permeability transition pores) and 2',3'-cAMP is converted to 2'-AMP and 3'-AMP, which in turn are metabolized to adenosine. Because the enzymes involved in this "2',3'-cAMP-adenosine pathway" are unknown, we examined whether 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) participates in the renal metabolism of 2',3'-cAMP. Western blotting and real-time PCR demonstrated expression of CNPase in rat glomerular mesangial, preglomerular vascular smooth muscle and endothelial, proximal tubular, thick ascending limb and collecting duct cells. Real-time PCR established the expression of CNPase in human glomerular mesangial, proximal tubular and vascular smooth muscle cells; and the level of expression of CNPase was greater than that for phosphodiesterase 4 (major enzyme for the metabolism of 3',5'-cAMP). Overexpression of CNPase in rat preglomerular vascular smooth muscle cells increased the metabolism of exogenous 2',3'-cAMP to 2'-AMP. Infusions of 2',3'-cAMP into isolated CNPase wild-type (+/+) kidneys increased renal venous 2'-AMP, and this response was diminished by 63% in CNPase knockout (-/-) kidneys, whereas the conversion of 3',5'-cAMP to 5'-AMP was similar in CNPase +/+ vs. -/- kidneys. In CNPase +/+ kidneys, energy depletion (metabolic poisons) increased kidney tissue levels of adenosine and its metabolites (inosine, hypoxanthine, xanthine, and uric acid) without accumulation of 2',3'-cAMP. In contrast, in CNPase -/- kidneys, energy depletion increased kidney tissue levels of 2',3'-cAMP and abolished the increase in adenosine and its metabolites. In conclusion, kidneys express CNPase, and renal CNPase mediates in part the renal 2',3'-cAMP-adenosine pathway.
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania; edj@pitt.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Gillespie
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania;
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Department of Neuroscience, University of Connecticut School of Medicine, Farmington, Connecticut;
authors.forename: Rashmi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Keri
authors.initials: K
authors.lastname: Janesko-Feldman
authors.affiliation: Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, Pennsylvania; and Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
mesh_terms: D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000378:metabolism*; D000241:Adenosine / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000249:Adenosine Monophosphate; D000242:Cyclic AMP; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D000241:Adenosine
keywords: 2′,3′-cyclic adenosine monophosphate; 2′,3′-cyclic nucleotide 3′-phosphodiesterase; 2′-adenosine monophosphate; 3′-adenosine monophosphate; CNPase; adenosine