Effect of Mycophenolic Acid and Rapamycin on the Proliferation of Glomerular Mesangial Cell of Rat

ABSTRACT

PURPOSE: Excess proliferation of mesenchymal cells such as vascular smooth muscle cells and glomerular mesangial cells, cause transplant vascular sclerosis and glomerulosclerosis, which are typical pathological lesions of chronic allograft dysfunction. Mycophenoic acid (MPA) and rapamycin (RPM) were recently reported to have strong anti-proliferative potentials toward vascular smooth muscle cells. However, the potential effects of these drugs, either alone or in combination, on glomerular mesangial cells, remain to be reported. METHODS: Primary cultured mesangial cells, from Sprague-Dawley rats, were isolated, and stimulated with 10ng/ml of PDGF. The test drugs MPA and RPM were administered at various concentrations, either alone or in combination, 15 minutes before the addition of the PDGF. The cell proliferation was assessed by [3H]-thymidine incorporation. RESULTS: The PDGF effectively stimulated the proliferation of the mesangial cells. The MPA inhibited the proliferation in a dose-dependent manner. In comparison to the stimulated control, the MPA (above 500 nM) showed a significant inhibitory effect. The IC50 of the MPA, against PDGF-stimulated mesangial cell proliferation, was between 500 nM and 1microM. The RPM, at 10 nM, showed a significant inhibitory effect. In a linear regression analysis, the RPM was supposed to suppress the mesangial proliferation in a dose-dependent manner (P<0.05). The pattern of inhibition for the MPA and RPM combination was very similar to that of either the MPA or the RPM alone. Both the MPA and RPM were shown to independently suppress the mesangial proliferation from a multiple regression analysis (R2=0.415, P<0.001). CONCLUSION: We demonstrated that MPA and RPM significantly inhibited the proliferation of glomerular mesangial cells, and that these effects were well maintained when used in combination. Our data indicate that both MPA and RPM have unique potentials in preventing the development of transplant mesangial proliferation in renal transplant recipients.