Extracellular 2,3-cyclic adenosine monophosphate is a potent inhibitor of preglomerular vascular smooth muscle cell and mesangial cell growth [corrected].
Recently we discovered that intact kidneys release into the extracellular compartment 2',3'-cAMP (a positional isomer of 3',5'-cAMP with unknown pharmacology) and metabolize 2',3'-cAMP to 2'-AMP, 3'-AMP, and adenosine. Because adenosine inhibits growth of vascular smooth muscle cells and mesangial cells, we tested the hypothesis that extracellular 2',3'-cAMP attenuates growth of preglomerular vascular smooth muscle and mesangial cells via production of adenosine. For comparison, all of the experiments were performed with both 2',3'-cAMP and 3',5'-cAMP. In study 1, 2',3'-cAMP, 3',5'-cAMP, 5'-AMP, 3'-AMP, or 2'-AMP was incubated with cells and purines measured in the medium by mass spectrometry. Both preglomerular vascular smooth muscle and mesangial cells metabolized 3',5'-cAMP to 5'-AMP and adenosine; 5'-AMP to adenosine; 2',3'-cAMP to 2'-AMP, 3'-AMP, and adenosine; and 2'-AMP and 3'-AMP to adenosine. 3-Isobutyl-1-methylxanthine (phosphodiesterase inhibitor) and 1,3-dipropyl-8-p-sulfophenylxanthine (ecto-phosphodiesterase inhibitor) blocked conversion of 3',5'-cAMP to 5'-AMP and adenosine, and alpha,beta-methylene-adenosine-5'-diphosphate (CD73 inhibitor) blocked conversion of 5'-AMP to adenosine. These enzyme inhibitors had little effect on metabolism of 2',3'-cAMP, 2'-AMP, or 3'-AMP. For study 2, 2',3'-cAMP and 3',5'-cAMP profoundly inhibited proliferation (thymidine incorporation and cell number) of both cell types, with 2',3'-cAMP more potent than 3',5'-cAMP. Antagonism of A(2B) receptors (MRS-1724), but not A(1) (1,3-dipropyl-8-cyclopentylxanthine), A(2A) (SCH-58261), or A(3) (VUF-5574) receptors, attenuated the growth inhibitory effects of 2',3'-cAMP and 3',5'-cAMP. Extracellular 2',3'-cAMP inhibits growth of preglomerular vascular smooth muscle and mesangial cells more profoundly than does 3',5'-cAMP. Although both cAMPs inhibit growth in part via conversion to adenosine followed by A(2B) receptor activation, their metabolism is mediated by different enzymes.
Jackson
Edwin K
EK
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, 100 Technology Dr, Suite 450, Pittsburgh, PA 15219, USA. edj@pitt.edu
Ren
Jin
J
Gillespie
Delbert G
DG
Dubey
Raghvendra K
RK
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002853:Chromatography, Liquid; D045604:Extracellular Fluid; D008297:Male; D050527:Mesangial Cells / Q000166:cytology* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000254:growth & development* / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D043704:Receptor, Adenosine A2B / Q000378:metabolism
D000227:Adenine Nucleotides; D043704:Receptor, Adenosine A2B; C010565:2',3'-cyclic AMP