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

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1561-1567
Number of pages7
JournalLife Sciences
Volume79
Issue number16
DOIs
Publication statusPublished - 2006 Sep 13

Fingerprint

Mycophenolic Acid
Mesangial Cells
p38 Mitogen-Activated Protein Kinases
Chemical activation
Cell proliferation
Extracellular Matrix
Cell Proliferation
Guanosine
Fibronectins
Allografts
Collagen
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Immunosuppressive Agents
Chronic Renal Insufficiency
Proline
Thymidine
Rats
Western Blotting

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Ha, Hunjoo ; Kim, Myoung Soo ; Park, Jehyun ; Huh, Joo Young ; Huh, Kyu Ha ; Ahn, Hyung Joon ; Kim, Yu Seun. / Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition. In: Life Sciences. 2006 ; Vol. 79, No. 16. pp. 1561-1567.
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abstract = "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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Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition. / Ha, Hunjoo; Kim, Myoung Soo; Park, Jehyun; Huh, Joo Young; Huh, Kyu Ha; Ahn, Hyung Joon; Kim, Yu Seun.

In: Life Sciences, Vol. 79, No. 16, 13.09.2006, p. 1561-1567.

Research output: Contribution to journalArticle

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T1 - Mycophenolic acid inhibits mesangial cell activation through p38 MAPK inhibition

AU - Ha, Hunjoo

AU - Kim, Myoung Soo

AU - Park, Jehyun

AU - Huh, Joo Young

AU - Huh, Kyu Ha

AU - Ahn, Hyung Joon

AU - Kim, Yu Seun

PY - 2006/9/13

Y1 - 2006/9/13

N2 - 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.

AB - 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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