Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition.
Mesangial cell (MC) proliferation and extracellular matrix (ECM) accumulation are major pathologic features of chronic renal disease including chronic allograft nephropathy (CAN). Mycophenolic acid (MPA), a potent immunosuppressant, has emerged as a treatment to prevent CAN because it inhibits MC proliferation and ECM synthesis, but the mechanism involved has not been clarified. The present study examined relative role of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) activation in inhibitory effect of MPA on MC activation. Growth arrested and synchronized primary rat MC (passages 7-11) were stimulated by PDGF 10 ng/ml in the presence and absence of clinically attainable dose of MPA (0-10 microM). Cell proliferation was assessed by [(3)H]thymidine incorporation, fibronectin and the activation of ERK and p38 MAPK by Western blot analysis, and total collagen by [(3)H]proline incorporation. PDGF increased cell proliferation by 4.6-fold, fibronectin secretion by 3.2-fold, total collagen synthesis by 1.8-fold, and the activation of ERK and 38 MAPK by 5.6-fold and 3.1-fold, respectively, compared to control. MPA, at doses inhibiting PDGF-induced MC proliferation and ECM synthesis, effectively blocked p38 MAPK activation but reduced ERK activation by 23% at maximal concentration tested (10 microM). Exogenous guanosine partially reversed the inhibition of MPA on p38 MAPK activation. Inhibitor of ERK or p38 MAPK suppressed PDGF-induced MC proliferation and ECM synthesis. In conclusion, MPA inhibits p38 MAPK activation leading to inhibiting proliferation and ECM synthesis in MC. Guanosine reduction is partially responsible for inhibitory effect of MPA on p38 MAPK activation in MC.
Ha
Hunjoo
H
Ewha Womans University College of Pharmacy, Seoul, South Korea.
Kim
Myoung Soo
MS
Park
Jehyun
J
Huh
Joo Young
JY
Huh
Kyu Ha
KH
Ahn
Hyung Joon
HJ
Kim
Yu Seun
YS
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins; D006151:Guanosine / Q000494:pharmacology; D050527:Mesangial Cells / Q000187:drug effects* / Q000201:enzymology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009173:Mycophenolic Acid / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D051381:Rats; D013936:Thymidine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000187:drug effects
D005353:Fibronectins; D010982:Platelet-Derived Growth Factor; D006151:Guanosine; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D009173:Mycophenolic Acid; D013936:Thymidine