Inhibition of human mesangial cell proliferation by calcium channel blockers.
Human mesangial cells in culture proliferate in response to platelet-derived growth factor (PDGF) and thrombin. Both of these agents also induce changes in cytosolic calcium that are dependent on both mobilization of intracellular calcium and influx of extracellular calcium. We hypothesized that calcium channel blockers, by preventing influx of extracellular calcium, may inhibit proliferation induced by these mitogens. We found that three different calcium channel blockers, diltiazem, nifedipine, and verapamil, were able to significantly inhibit [3H]thymidine incorporation into human mesangial cells induced by either PDGF or thrombin. The inhibitory effect of these agents was significant at 10(-5) M. The calcium channel blockers also attenuated the increases in cell number and percentage of labeled nuclei induced by these mitogens. In contrast, dantrolene, an inhibitor of intracellular calcium mobilization, had no significant effect on [3H]thymidine incorporation by PDGF or thrombin. Finally, the calcium channel agonist, Bay K 8644 was found to stimulate [3H]thymidine incorporation into mesangial cells. Although the mechanisms for these effects of calcium channel blockers are not proven, these studies suggest that influx of extracellular calcium is an important signal in mitogen-induced mesangial proliferation and that these agents can be beneficial in preventing or attenuating renal diseases characterized by proliferation of these cells.
Department of Medicine, VA Medical Center, University of Minnesota, Minneapolis 55417.
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PJ
Shultz
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Raij
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003620:Dantrolene / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D005920:Glomerular Mesangium / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D009543:Nifedipine / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D010982:Platelet-Derived Growth Factor; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D014700:Verapamil; D013917:Thrombin; D004110:Diltiazem; D003620:Dantrolene; D009543:Nifedipine; D013936:Thymidine