Document Detail

Calcium channel blockers inhibit proliferation and matrix production in rat mesangial cells: possible mechanism of suppression of AP-1 and CREB activities.
MedLine Citation:
PMID:  10773759     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Calcium channel blockers (CCBs) are reported to attenuate the loss of renal function in various glomerulonephritides. METHODS: To determine the mechanism of action of these drugs, we investigated the effects of CCBs on cell proliferation and extracellular matrix (ECM) production in cultured rat mesangial cells. RESULTS: While stimulation with 5% fetal calf serum (FCS) increased [(3)H]thymidine and [(3)H]proline incorporation into quiescent mesangial cells, incubation with nifedipine and cilnidipine inhibited the increase in a dose-dependent manner. Northern blot analysis demonstrated that 5% FCS increased the expression of transforming growth factor beta (TGF-beta) and fibronectin (FN) mRNA and that CCBs significantly reduced this induction, indicating that CCBs may reduce ECM production through inhibiting TGF-beta and FN. Since activator protein 1 (AP-1) regulates cell proliferation and TGF-beta expression, we evaluated the AP-1 activity by gel mobility shift analysis. Nuclear extracts of FCS-treated cells showed a strong binding to AP-1-specific oligonucleotides which was suppressed by CCBs, suggesting that these agents may inhibit cell proliferation by suppressing AP-1. CCBs also inhibited the binding activity of cyclic adenosine monophosphate responsive element binding protein which regulates FN gene expression. However, neither CCBs nor FCS affected the NFkappaB activity. CONCLUSION: These results suggest that CCBs may, in part, inhibit the progression of glomerulonephritis through non-hemodynamic actions that include the suppression of mesangial cell proliferation and the production of ECM.
T Sugiura; E Imai; T Moriyama; M Horio; M Hori
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Nephron     Volume:  85     ISSN:  0028-2766     ISO Abbreviation:  Nephron     Publication Date:  2000 May 
Date Detail:
Created Date:  2000-07-21     Completed Date:  2000-07-21     Revised Date:  2005-11-17    
Medline Journal Info:
Nlm Unique ID:  0331777     Medline TA:  Nephron     Country:  SWITZERLAND    
Other Details:
Languages:  eng     Pagination:  71-80     Citation Subset:  IM    
Copyright Information:
Copyright 2000 S. Karger AG, Basel
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Japan.
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MeSH Terms
Blotting, Northern
Calcium Channel Blockers / pharmacology*
Cell Division / drug effects
Cells, Cultured
Collagen / genetics
Cyclic AMP Response Element-Binding Protein / metabolism*
Dihydropyridines / pharmacology
Extracellular Matrix / metabolism*
Fibronectins / genetics
Gene Expression / drug effects
Glomerular Mesangium / cytology,  drug effects*,  metabolism
Nifedipine / pharmacology*
Proto-Oncogene Proteins c-fos / analysis,  immunology,  metabolism
Proto-Oncogene Proteins c-jun / analysis,  immunology,  metabolism
RNA, Messenger / analysis
Thymidine / metabolism,  pharmacology
Transcription Factor AP-1 / metabolism*
Transforming Growth Factor beta / genetics
Tritium / diagnostic use
Reg. No./Substance:
0/Antibodies; 0/Calcium Channel Blockers; 0/Cyclic AMP Response Element-Binding Protein; 0/Dihydropyridines; 0/Fibronectins; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/RNA, Messenger; 0/Transcription Factor AP-1; 0/Transforming Growth Factor beta; 10028-17-8/Tritium; 132203-70-4/cilnidipine; 21829-25-4/Nifedipine; 50-89-5/Thymidine; 9007-34-5/Collagen

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