Departments of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, USA.
J Biol Chem. 2009 Nov 27;284(48):33097-106. doi: 10.1074/jbc.M109.053876. Epub 2009 Oct 1.
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).
我们发现肾损伤会将 2'，3'-cAMP（3'，5'-cAMP 的位置异构体）释放到间质中。这一发现激发了一个新的假说：肾损伤会导致细胞外 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，然后代谢为腺苷，一种报复性代谢物）。在分离的大鼠肾脏中，动脉输注 2'，3'-cAMP（30µmol/L）会使静脉分泌的 3'-AMP（3400 倍）、2'-AMP（26000 倍）、腺苷（53 倍）和肌苷（腺苷代谢物，30 倍）增加。用代谢抑制剂引起肾损伤会使 2'，3'-cAMP（29 倍）、3'-AMP（16 倍）、2'-AMP（10 倍）、腺苷（4.2 倍）和肌苷（6.1 倍）的平均分泌量增加，而 5'-AMP（2.4 倍）略有增加。动脉输注 2'-AMP 和 3'-AMP 会增加腺苷和肌苷的分泌，与 5'-AMP 相似。体内肾动脉输注 2'，3'-cAMP 会增加 2'-AMP、3'-AMP 和腺苷的尿排泄，而输注 2'-AMP 和 3'-AMP 与 5'-AMP 一样有效地增加腺苷的尿排泄。这意味着：1）在完整的器官中，2'-AMP 和 3'-AMP 转化为腺苷的效率与 5'-AMP（以前被认为是最重要的腺苷前体）一样高；2）由于 2'，3'-cAMP 打开线粒体通透性转换孔，这是一种促凋亡/促坏死的过程，细胞外 2'，3'-cAMP-腺苷途径将 2'，3'-cAMP 转化为腺苷，这将通过减少促死亡因子（2'，3'-cAMP）并增加报复性代谢物（腺苷）来保护组织。
