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(Hypertension. 2005;46:628.)
© 2005 American Heart Association, Inc.

Original Articles

Adenosine Inhibits PDGF-Induced Growth of Human Glomerular Mesangial Cells Via A_2B Receptors

Raghvendra K. Dubey; Delbert G. Gillespie; Zaichuan Mi; Edwin K. Jackson

From the Center for Clinical Pharmacology, Departments of Medicine (R.K.D., D.G.G., Z.M., E.K.J.) and Pharmacology (E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Pa, and the Clinic for Endocrinology (R.K.D.), Department of Obstetrics and Gynecology, University Hospital Zurich, Zurich, Switzerland.

Correspondence to Dr Raghvendra K. Dubey, Department of Obstetrics and Gynecology Clinic for Endocrinology, D215 NORD-1, Frauenklinik University Hospital Zurich, 8091 Zurich, Switzerland. E-mail Raghvendra.dubey{at}usz.ch

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 by N⁶-cyclopentyladenosine (selective A₁ AR agonist), AB-N-MECA (selective A₃ AR agonist), or CGS21680(selective A_2A AR agonist). KF17837 (selective A_2A/B AR antagonist) and 1,3-dipropyl-8-p-sulfophenylxanthine (nonselective AR antagonist), but not 8-cyclopentyl-1,3-dipropylxanthine (selective A₁ AR antagonist), blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-MECA. Antisense, but not sense or scrambled, oligonucleotides to the A_2B receptor increased both basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis, and the growth-inhibitory effects of 2-chloroadenosine, 5'-N-MECA, and erythro-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 A_2B receptor. We conclude that adenosine causes inhibition of GMC growth by activating A_2B receptors coupled to inhibition of MAPK activity. A_2B receptors may play an important role in regulating glomerular remodeling associated with GMC proliferation. Pharmacological or molecular biologic activation of A_2B receptors may prevent glomerular remodeling associated with glomerulosclerosis, renal disease, and abnormal growth associated with hypertension and diabetes.

Key Words: adenosine • mesangium • receptors, adenine • remodeling • glomerulosclerosis • renal disease • kidney

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