Mycophenolic acid antagonizes the activation of cultured human mesangial cells

Background. Activation of mesangial cells is observed in several forms of chronic renal disease, and in culture conditions upon stimulation by fetal calf serum (FCS), or agonists such as transforming growth factor beta (TGF-beta). Mycophenolate mofetil (MMF), the precursor of mycophenolic acid (MPA), is currently used in organ transplantation and has been shown to be protective in clinical and experimental glomerulonephritis. This study assessed the effects of MPA on markers of human mesangial cells (HMC) activation. Methods. Primary cultures of HMC and of an immortalized HNIC clone (IP15 cells characterized in this report) were stimulated either by FCS or by TGF-beta, and treated by MPA at clinically relevant concentrations (1 to 10 mumol/L) for 24 hours to 14 days. HNIC proliferation, smooth muscle alpha-actin (SMA), collagen type I alpha-1 chain (coll I) and fibronectin synthesis were used as markers of HNIC phenotypic activation. Results. Exposure of HNIC to MPA inhibited proliferation induced by FCS without cytotoxicity. MPA counteracted the stimulatory effects of FCS and TGF-beta on coll I mRNA and protein and fibronectin protein. SMA expression was increased upon exposure to MPA, without cell hypertrophy. Conclusion. Treatment of cultured HNIC with MPA inhibited mesangial cell proliferation and matrix production induced by stimulation with either FCS or TGF-beta. Such mechanisms may contribute to the favorable effects of treatment using mycophenolate mofetil in chronic fibrotic kidney diseases, including chronic allograft rejection.