Extracellular 2',3'-cAMP is a source of adenosine.
We discovered that renal injury releases 2',3'-cAMP (positional isomer of 3',5'-cAMP) into the interstitium. This finding motivated a novel hypothesis: renal injury leads to activation of an extracellular 2',3'-cAMP-adenosine pathway (i.e. metabolism of extracellular 2',3'-cAMP to 3'-AMP and 2'-AMP, which are metabolized to adenosine, a retaliatory metabolite). In isolated rat kidneys, arterial infusions of 2',3'-cAMP (30 mumol/liter) increased the mean venous secretion of 3'-AMP (3,400-fold), 2'-AMP (26,000-fold), adenosine (53-fold), and inosine (adenosine metabolite, 30-fold). Renal injury with metabolic inhibitors increased the mean secretion of 2',3'-cAMP (29-fold), 3'-AMP (16-fold), 2'-AMP (10-fold), adenosine (4.2-fold), and inosine (6.1-fold) while slightly increasing 5'-AMP (2.4-fold). Arterial infusions of 2'-AMP and 3'-AMP increased secretion of adenosine and inosine similar to that achieved by 5'-AMP. Renal artery infusions of 2',3'-cAMP in vivo increased urinary excretion of 2'-AMP, 3'-AMP and adenosine, and infusions of 2'-AMP and 3'-AMP increased urinary excretion of adenosine as efficiently as 5'-AMP. The implications are that 1) in intact organs, 2'-AMP and 3'-AMP are converted to adenosine as efficiently as 5'-AMP (previously considered the most important adenosine precursor) and 2) because 2',3'-cAMP opens mitochondrial permeability transition pores, a pro-apoptotic/pro-necrotic process, conversion of 2',3'-cAMP to adenosine by the extracellular 2',3'-cAMP-adenosine pathway would protect tissues by reducing a pro-death factor (2',3'-cAMP) while increasing a retaliatory metabolite (adenosine).
Departments of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, USA. edj@pitt.edu
Edwin K
EK
Jackson
Jin
J
Ren
Zaichuan
Z
Mi
D000227:Adenine Nucleotides / Q000378:metabolism* / Q000493:pharmacokinetics; D000241:Adenosine / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005110:Extracellular Space / Q000378:metabolism*; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D053719:Tandem Mass Spectrometry
D000227:Adenine Nucleotides; D000249:Adenosine Monophosphate; C010565:2',3'-cyclic AMP; D000241:Adenosine