Extracellular 2′,3′-cAMP Is a Source of Adenosine
Extracellular 2′,3′-cAMP Is a Source of Adenosine
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DOI：
10.1074/jbc.m109.053876
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发表时间：
2009-11-27
影响因子：
4.8
通讯作者：
Mi, Zaichuan
中科院分区：
文献类型：
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作者：
Jackson, Edwin K.;Ren, Jin;Mi, Zaichuan
我们发现，肾损伤释放2 '，3'-cAMP（3 '，5'-cAMP的位置异构体）进入肾小管。这一发现激发了一种新的假设：肾损伤导致细胞外2 '，3'-cAMP-腺苷途径的激活（即细胞外2 '，3'-cAMP代谢为3 '-AMP和2'-AMP，它们代谢为腺苷，一种报复性代谢物）。在离体大鼠肾脏中，动脉输注2 '，3'-cAMP（30 μ mol/L）可增加3 '-AMP（3，400倍）、2'-AMP（26，000倍）、腺苷（53倍）和肌苷（腺苷代谢物，30倍）的平均静脉分泌。使用代谢抑制剂的肾损伤增加了2 '，3'-cAMP（29倍）、3 '-AMP（16倍）、2'-AMP（10倍）、腺苷（4.2倍）和肌苷（6.1倍）的平均分泌，同时略微增加了5 '-AMP（2.4倍）。动脉灌注2 '-AMP和3'-AMP增加腺苷和肌苷的分泌，与5 '-AMP相似。肾动脉灌注2 '，3'-cAMP可增加2 '-AMP、3'-AMP和腺苷的尿排泄量，2 '-AMP和3'-AMP可增加腺苷的尿排泄量，其效果与5 '-AMP相当。结果表明：1）在完整器官中，2 ′-AMP和3 ′-AMP转化为腺苷的效率与5 ′-AMP一样高（以前认为是最重要的腺苷前体）和2）由于2 '，3'-cAMP打开线粒体通透性转换孔，这是一种促凋亡/促坏死过程，2 '，3'-cAMP通过细胞外2 '，3 '-cAMP-腺苷途径将通过减少促死亡因子（2'，3 '-cAMP）同时增加报复性代谢物（腺苷）来保护组织。
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 mu mol/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/pronecrotic 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).