title: Mesangial cell apoptosis induced by stimulation of the adenosine A3 receptor: signaling and apoptotic events.
abstract: Mesangial cell apoptosis has been proposed as a means of resolution of glomerular hypercellularity in proliferative forms of glomerular disease. We previously demonstrated that adenosine causes mesangial cell apoptosis by stimulating the A3-type adenosine receptor. This is a G protein-coupled receptor shown to activate kinases involved in apoptotic signaling. In this work, we assessed changes in phosphorylation of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK)1/2 and in levels of specific pro- and antiapoptotic proteins following exposure of mesangial cells to the A3 adenosine receptor agonist N(6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA). Cultured mesangial cells were incubated with IB-MECA for 30 minutes and 6, 24, and 48 hours. IB-MECA was used at a concentration (30 microM) that induces a reproducible degree of mesangial cell apoptosis. Changes in ERK1/2 phosphorylation and in protein levels of Bcl-2, Bax, and caspase 3 were assessed by Western blot analysis. IB-MECA markedly increased phosphorylation of ERK1/2. This effect peaked at 5 minutes, dissipated by 20 minutes, and was abolished by the inhibitor of ERK phosphorylation, compound U0126, in a dose-dependent manner. This inhibitor had no effect on the extent of IB-MECA-induced apoptosis. Bcl-2 levels progressively declined, whereas those of Bax and activated caspase 3 increased. These observations indicate that stimulation of the A3-type adenosine receptor causes mesangial cell apoptosis via mechanisms independent of ERK activation. The observations also point to an imbalance in the expression of antiapoptotic (Bcl-2) and proapoptotic (Bax, caspase 3) proteins as a potential mechanism underlying adenosine-induced mesangial cell apoptosis.
authors: Department of Medicine, Nephrology Division, Robert Wood Johnson Medical School, New Brunswick, NJ 0903-0019, USA.
authors: Pu
authors: P
authors: Duann
authors: Teh-Yuan
authors: TY
authors: Ho
authors: Bijal D
authors: BD
authors: Desai
authors: Toros
authors: T
authors: Kapoian
authors: Daniel S
authors: DS
authors: Cowen
authors: Elias A
authors: EA
authors: Lianos
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D005920:Glomerular Mesangium / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D002070:Butadienes; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; D043684:Receptor, Adenosine A3; C113580:U 0126; D051028:bcl-2-Associated X Protein; C084956:N(6)-(3-iodobenzyl)-5'-N-methylcarboxamidoadenosine; D019950:Mitogen-Activated Protein Kinase 1; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D000241:Adenosine