Adenosine Inhibits PDGF-Induced Growth of Human Glomerular Mesangial Cells Via A2BReceptors

Publisher Website
Google Scholar
Abstract
The objectives of the present study were to determine whether adenosine attenuates proliferation of glomerular mesangial cells (GMCs), which adenosine receptor (AR) mediates the antimitogeneic actions of adenosine, and the cellular mechanisms by which adenosine inhibits growth of GMCs. Studies were conducted in both human and rat GMCs. Platelet-derived growth factor (PDGF)-BB (25 ng/mL) increased DNA synthesis ([3H]thymidine incorporation), cellular proliferation (cell number), collagen synthesis ([3H]proline incorporation), and mitogen-activated protein kinase (MAPK) activity, and these effects were attenuated by 2-chloroadenosine (nonselective AR agonist) and 5′-N-methylcarboxamidoadenosine (MECA; nonselective AR agonist), but not byN6-cyclopentyladenosine (selective A1AR agonist), AB-N-MECA (selective A3AR agonist), or CGS21680 (selective A2AAR agonist). KF17837 (selective A2A/BAR antagonist) and 1,3-dipropyl-8-p-sulfophenylxanthine (nonselective AR antagonist), but not 8-cyclopentyl-1,3-dipropylxanthine (selective A1AR antagonist), blocked the growth-inhibitory effects of 2-chloroadenosine and 5′-N-MECA. Antisense, but not sense or scrambled, oligonucleotides to the A2Breceptor increased both basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis, and the growth-inhibitory effects of 2-chloroadenosine, 5′-N-MECA, anderythro-9-(2-hydroxy-3-nonyl)adenine (inhibitor of adenosine deaminase) plus iodotubercidin (inhibitor of adenosine kinase) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A2Breceptor. We conclude that adenosine causes inhibition of GMC growth by activating A2Breceptors coupled to inhibition of MAPK activity. A2Breceptors may play an important role in regulating glomerular remodeling associated with GMC proliferation. Pharmacological or molecular biologic activation of A2Breceptors may prevent glomerular remodeling associated with glomerulosclerosis, renal disease, and abnormal growth associated with hypertension and diabetes.