Mycophenolic acid: a new approach to the therapy of experimental mesangial proliferative glomerulonephritis.

Mycophenolate mofetil (MMF) represents a powerful immunosuppressant in organ transplantation. The aim of this study was to determine the anti-inflammatory effects of MMF on mesangial cells. Cultured rat mesangial cells were exposed to mycophenolic acid (MPA) in concentrations of 0.1 to 10 �tM. MPA inhibited the proliferation of these cells in a dose- dependent manner. A maximum of 98% inhibition was ob- tamed by a 2-d exposure of mesangial cells to �5 j.�M MPA. As expected, the addition of �75 jtM guanosine prevented the antiproliferative effect of MPA completely. Subsequently, in vivo studies were performed in the anti-Thy 1 . I nephritis model. Sixty-six male Wistar rats were investigated: healthy rats (n = 15), treated healthy rats (ii = 6), nephritic rats (a = I 5), and treated nephritic rats (n = 30). MMF therapy (40 mg/kg body wt per d) of nephritic animals was initiated 2 d before (n = 3) and 6 h (a I 5) or 2 d (ii I 2) after induction of nephritis. Renal histology was analyzed at days +6 and +9 after initiation of disease. Therapy of nephritic rats by MMF resulted in a significant amelioration of glomerular histology, assessed by glomerubar cellularity, synthesis of a-smooth mus- cle actin, extracellubar matrix deposition, and gbomerular hy- pertrophy. Proteinuria, expressed as areas under the curve of protein/creatinine ratios versus time, showed a clear tendency toward a reduction by MMF therapy. Healthy control rats were not negatively affected by exposure to MMF. In summary, this study shows that mesangial cell proliferation can be signifi- cantly inhibited by MPA in vitro and in vivo. MMF represents a new approach to the therapy of experimental mesangial cell-mediated forms of gbomerulonephritis.