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 HMC 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 micromol/L) for 24 hours to 14 days. HMC proliferation, smooth muscle alpha-actin (SMA), collagen type I alpha-1 chain (coll I) and fibronectin synthesis were used as markers of HMC phenotypic activation.


RESULTS
Exposure of HMC 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.


CONCLUSIONS
Treatment of cultured HMC 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.
Dubus
Isabelle
I
Unité INSERM 441 Avenue du Haut Lévêque, 33600 Pessac, France. dubus@biophar.u-bordeaux2.fr
Vendrely
Benoît
B
Christophe
Isabelle
I
Labouyrie
Jean-Pierre
JP
Delmas
Yahsou
Y
Bonnet
Jacques
J
Combe
Christian
C
D000199:Actins / Q000235:genetics; D015415:Biomarkers; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005353:Fibronectins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D009173:Mycophenolic Acid / Q000494:pharmacology*; D010641:Phenotype; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000199:Actins; D015415:Biomarkers; C000716127:COL1A1 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D016212:Transforming Growth Factor beta; D009173:Mycophenolic Acid