Extracellular 2′,3′-cAMP Is a Source of Adenosine*

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American Society for Biochemistry and Molecular Biology

RESUMO

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 μmol/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).

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