Dept. of Pharmacology and Chemical Biology, 100 Technology Dr., Rm. 514, Univ. of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
Am J Physiol Renal Physiol. 2012 Oct;303(7):F954-62. doi: 10.1152/ajprenal.00335.2012. Epub 2012 Jul 11.
Kidneys release into the extracellular compartment 3',5'-cAMP and its positional isomer 2',3'-cAMP. The purpose of the present study was to investigate the metabolism of extracellular 2',3'-cAMP and 3',5'-cAMP in preglomular vascular endothelial and proximal tubular epithelial cells and to determine whether these cAMPs and their downstream metabolites affect cellular proliferation. In preglomerular vascular endothelial and proximal tubular epithelial cells, 1) extracellular 2',3'-cAMP increased extracellular levels of 3'-AMP and 2'-AMP, whereas extracellular 3',5'-cAMP increased extracellular levels of 5'-AMP; 2) extracellular 5'-AMP, 3'-AMP, and 2'-AMP increased extracellular adenosine; 3) α,β-methylene-adenosine-5'-diphosphate (CD73 inhibitor) prevented the 5'-AMP-induced increase in extracellular adenosine in preglomerular vascular endothelial cells, but did not affect the 5'-AMP-induced increase in extracellular adenosine in proximal tubular cells or the 3'-AMP-induced or 2'-AMP-induced increase in extracellular adenosine in either cell type; 4) extracellular 2',3'-cAMP, 3'-AMP, 2'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine stimulated proliferation of both preglomerular vascular endothelial and proximal tubular cells; and 5) MRS-1754 (selective A(2B) receptor antagonist) abolished the progrowth effects of extracellular 2',3'-cAMP, 3'-AMP, 2'-AMP, 3',5'-cAMP, 5'-AMP, and adenosine in both cell types. Extracellular 2',3'-cAMP and 3',5'-cAMP stimulate proliferation of preglomerular vascular endothelial cells and proximal tubular cells. The mechanism by which the cAMPs increase cell proliferation entails 1) metabolism to their respective AMPs, 2) metabolism of their respective AMPs to adenosine (which for 5'-AMP in preglomerular vascular endothelial cells is mediated by CD73), and 3) activation of A(2B) receptors. Both extracellular 2',3'-cAMP and 3',5'-cAMP may help restore architecture of the preglomerular microcirculation and tubular system following kidney injury.
肾脏将 3'，5'-cAMP 和其位置异构体 2'，3'-cAMP 释放到细胞外腔室。本研究的目的是研究肾小球血管内皮细胞和近端肾小管上皮细胞中外源 2'，3'-cAMP 和 3'，5'-cAMP 的代谢，并确定这些 cAMPs 及其下游代谢物是否会影响细胞增殖。在肾小球血管内皮细胞和近端肾小管上皮细胞中，1）细胞外 2'，3'-cAMP 增加了细胞外 3'-AMP 和 2'-AMP 的水平，而细胞外 3'，5'-cAMP 增加了细胞外 5'-AMP 的水平；2）细胞外 5'-AMP、3'-AMP 和 2'-AMP 增加了细胞外腺苷；3）α，β-亚甲基-腺苷-5'-二磷酸（CD73 抑制剂）阻止了 5'-AMP 诱导的肾小球血管内皮细胞中细胞外腺苷的增加，但不影响 5'-AMP 诱导的近端肾小管细胞中细胞外腺苷的增加，或 3'-AMP 诱导或 2'-AMP 诱导的两种细胞类型中细胞外腺苷的增加；4）细胞外 2'，3'-cAMP、3'-AMP、2'-AMP、3'，5'-cAMP、5'-AMP 和腺苷均刺激肾小球血管内皮细胞和近端肾小管细胞的增殖；5）MRS-1754（选择性 A2B 受体拮抗剂）消除了细胞外 2'，3'-cAMP、3'-AMP、2'-AMP、3'，5'-cAMP、5'-AMP 和腺苷在两种细胞类型中的促生长作用。细胞外 2'，3'-cAMP 和 3'，5'-cAMP 刺激肾小球血管内皮细胞和近端肾小管细胞的增殖。cAMPs 增加细胞增殖的机制包括 1）代谢为各自的 AMPs，2）各自的 AMPs 代谢为腺苷（在肾小球血管内皮细胞中，5'-AMP 通过 CD73 介导），以及 3）激活 A2B 受体。细胞外 2'，3'-cAMP 和 3'，5'-cAMP 都可能有助于在肾损伤后恢复肾小球微循环和管状系统的结构。
