TY - JOUR T1 - Extracellular 3′,5′-cAMP-Adenosine Pathway Inhibits Glomerular Mesangial Cell Growth JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 808 LP - 815 DO - 10.1124/jpet.110.166371 VL - 333 IS - 3 AU - Raghvendra K. Dubey AU - Marinella Rosselli AU - Delbert G. Gillespie AU - Zaichuan Mi AU - Edwin K. Jackson Y1 - 2010/06/01 UR - http://jpet.aspetjournals.org/content/333/3/808.abstract N2 - Abnormal growth of glomerular mesangial cells (GMCs) contributes to the pathophysiology of many types of nephropathy. Because adenosine is an autocrine/paracrine factor that potentially could regulate GMC proliferation and because the extracellular 3′,5′-cAMP-adenosine pathway (i.e., the conversion of extracellular 3′,5′-cAMP to 5′-AMP and adenosine on the cell surface) could generate adenosine in the biophase of GMC receptors, we investigated the role of the 3′,5′-cAMP-adenosine pathway in modulating growth [cell proliferation, DNA synthesis ([3H]thymidine incorporation), collagen synthesis ([3H]proline incorporation), and mitogen-activated protein kinase activity] of GMCs. The addition of exogenous 3′,5′-cAMP to human GMCs increased extracellular levels of 5′-AMP, adenosine, and inosine, and 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor), 1,3-dipropyl-8-p-sulfophenylxanthine (ecto-phosphodiesterase inhibitor), and α,β-methylene-adenosine-5′-diphosphate (ecto-5′-nucleotidase inhibitor) attenuated the increases in adenosine and inosine. Forskolin augmented extracellular 3′,5′-cAMP and adenosine concentrations, and 2′,5′-dideoxyadenosine (adenylyl cyclase inhibitor) blocked these increases. Exogenous 3′,5′-cAMP and forskolin inhibited all indices of cell growth, and antagonism of A2 [(E)-8-(3,4-dimethoxystyryl)-1,3-dipropyl-7-methylxanthine, KF17837] or A1/A2 (1,3-dipropyl-8-p-sulfophenylxanthine, DPSPX), but not A1 (8-cyclopentyl-1,3-dipropylxanthine), or A3{N-(2-methoxyphenyl)-N′-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF5574}, adenosine receptors blocked the growth-inhibitory actions of exogenous 3′,5′-cAMP, but not the effects of 8-bromo-3′,5′-cAMP (stable 3′,5′-cAMP analog). Erythro-9-(2-hydroxy-3-nonyl)adenine (adenosine deaminase inhibitor) plus 5-iodotubercidin (adenosine kinase inhibitor) enhanced the growth inhibition by exogenous 3′,5′-cAMP and forskolin, and A2 receptor antagonism blocked this effect. In rat GMCs, down-regulation of A2B receptors with antisense, but not sense or scrambled, oligonucleotides abrogated the inhibitory effects of 3′,5′-cAMP and forskolin on cell growth. The extracellular 3′,5′-cAMP-adenosine pathway exists in GMCs and attenuates cell growth via A2B receptors. Pharmacological augmentation of this pathway could abate pathological glomerular remodeling. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -