2′-AMP and 3′-AMP Inhibit Proliferation of Preglomerular Vascular Smooth Muscle Cells and Glomerular Mesangial Cells via A2B Receptors

Studies show that kidneys produce 2',3'-cAMP, 2',3'-cAMP is exported and metabolized to 2'-AMP and 3'-AMP, 2'-AMP and 3'-AMP are metabolized to adenosine, 2',3'-cAMP inhibits proliferation of preglomerular vascular smooth muscle cells (PGVSMCs) and glomerular mesangial cells (GMCs), and A(2B) (not A(1), A(2A), or A(3)) adenosine receptors mediate part of the antiproliferative effects of 2',3'-cAMP. These findings suggest that extracellular 2',3'-cAMP attenuates proliferation of PGVSMCs and GMCs partly via conversion to corresponding AMPs, which are metabolized to adenosine that activates A(2B) receptors. This hypothesis predicts that extracellular 2'-AMP and 3'-AMP should exert A(2B) receptor-mediated antiproliferative effects. Therefore, we examined the antiproliferative effects (cell counts) of 2'-AMP and 3'-AMP. In PGVSMCs and GMCs, 2'-AMP and 3'-AMP exerted concentration-dependent antiproliferative effects. 3'-AMP was equipotent with and 2'-AMP was 3-fold less potent than 5'-AMP (prototypical adenosine precursor). In PGVSMCs, the effects of 2'-AMP and 3'-AMP were mimicked by adenosine, and 8-[4-[((4-cyanophenyl)carbamoylmethyl)oxy]phenyl]-1,3-di(n-propyl)xanthine (MRS-1754) (A(2B) receptor antagonist) equally blocked the antiproliferative effects of 2'-AMP, 3'-AMP, and adenosine but less effectively blocked the effects of 2',3'-cAMP. Similar results were obtained in GMCs except that MRS-1754 also incompletely blocked the effects of 3'-AMP. We conclude that in PGVSMCs, 2'-AMP and 3'-AMP are antiproliferative, the antiproliferative effects of 2'-AMP and 3'-AMP are mediated nearly entirely by adenosine/A(2B) receptors, and some of the antiproliferative effects of 2',3'-cAMP are independent of adenosine/A(2B) receptors. Similar conclusions apply to GMCs except that 3'-AMP also has actions independent of adenosine/A(2B) receptors. Because A(2B) receptors are renoprotective, 2'-AMP and 3'-AMP may provide renoprotection by generating adenosine that activates A(2B) receptors.