Rapamycin Inhibits Platelet-Derived Growth Factor- Induced Collagen, but Not Fibronectin, Synthesis in Rat Mesangial Cells

Rapamycin, a macrocyclic lactone, is effective in reducing the incidence of acute rejection after renal transplantation. The inhibitory effects of rapamycin on lymphocyte proliferation and the molecular mechanisms that were involved have been described. However, its effects on glomerular mesangial cells have not been clearly understood, and here, we examined the effect of rapamycin on platelet-derived growth factor (PDGF) - induced extracellular matrix synthesis as well as cell proliferation in mesangial cells. Rat mesangial cells were isolated from the glomeruli of Sprague-Dawley rats and cultured with Dulbecco's modified Eagles medium containing 20% fetal bovine serum. Different concentrations of rapamycin were administered 1 hour before the addition of 10 ng/ml of PDGF into growth arrested and synchronized cells. Cell proliferation was assessed by [3H]thymidine incorporation, total collagen synthesis by [3H]proline incorporation, and fibronectin secretion into the medium by Western blot analysis. In the mesangial cells, PDGF increased cell proliferation by 4.6-fold, total collagen synthesis by 1.8-fold, and fibronectin secretion by 3.2-fold. Rapamycin above 10 nM significantly inhibited PDGF-induced proliferation and collagen synthesis, but the treatment of rapamycin up to 1micrometer did not show any significant effects on PDGF-induced fibronectin secretion. These inhibitory effects of rapamycin on PDGF-induced mesangial cell proliferation and collagen synthesis reflect the potential value of rapamycin in the prevention and treatment of glomerulosclerosis in patients with chronic allograft nephropathy.

Influence of co-dergocrine on platelet aggregation

In the present investigation, we studied the influence of co-dergocrine mesylate (dihydroergotoxin mesylate) on platelet aggregation induced by adrenaline, adenosine diphosphate (ADP) and collagen in vitro. Platelet-rich plasma was incubated with increasing concentrations of co-dergocrine (1.5, 3.0, 6.0, 12.0, and 48.0 microng/ml). The lowest concentration of co-dergocrine tested (1.5 microng/ml) inhibited adrenaline-induced aggregation by 97%. Higher concentrations of the compound caused similar degress of inhibition. ADP-induced aggregation was only decreased significantly (20%, P < 0.001) by the highest concentration of co-dergocrine, whereas collagen-induced aggregation was not affected. Our results demonstrate that co-dergocrine selectively inhibits platelet aggregation triggered by adrenaline in vitro