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Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition

 Hunjoo Ha  ;  Myoung Soo Kim  ;  Jehyun Park  ;  Joo Young Huh  ;  Kyu Ha Huh  ;  Hyung Joon Ahn  ;  Yu Seun Kim 
 LIFE SCIENCES, Vol.79(16) : 1561-1567, 2006 
Journal Title
Issue Date
Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Enzyme Activation/drug effects ; Extracellular Matrix/drug effects ; Extracellular Matrix/metabolism ; Fibronectins ; Guanosine/pharmacology ; Mesangial Cells/drug effects* ; Mesangial Cells/enzymology ; Mitogen-Activated Protein Kinase 3/metabolism ; Mycophenolic Acid/pharmacology* ; Platelet-Derived Growth Factor/pharmacology ; Rats ; Thymidine/metabolism ; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors* ; p38 Mitogen-Activated Protein Kinases/drug effects
Mycophenolic acid ; Mesangial cell ; Proliferation ; Extracellular matrix ; p38 mitogen-activated protein kinase
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 μM). Cell proliferation was assessed by [3H]thymidine incorporation, fibronectin and the activation of ERK and p38 MAPK by Western blot analysis, and total collagen by [3H]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 μM). 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.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Myoung Soo(김명수) ORCID logo https://orcid.org/0000-0002-8975-8381
Kim, Yu Seun(김유선) ORCID logo https://orcid.org/0000-0002-5105-1567
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