Pioglitazone inhibits high glucose-induced synthesis of extracellular matrix by NF-κB and AP-1 pathways in rat peritoneal mesothelial cells.
Mol Med Rep
; 7(4): 1336-42, 2013 Apr.
Article
em En
| MEDLINE
| ID: mdl-23404530
ABSTRACT
High glucose (HG) in peritoneal dialysates has been demonstrated to induce extracellular matrix (ECM) synthesis by peritoneal mesothelial cells (PMCs) and to contribute to peritoneal fibrosis during continuous ambulatory peritoneal dialysis (CAPD). In the present study, we investigated the effects of pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, on HG-induced ECM accumulation and the underlying mechanism in rat PMCs (RPMCs). In cultured RPMCs, HG treatment increased the expression of fibronectin (FN), collagen I and plasminogen activation inhibitor-1 (PAI-1) at the mRNA and protein levels, while it downregulated the expression of PPARγ in a time- and concentration-dependent manner. Pretreatment with pioglitazone not only decreased the expression of PAI-1 and matrix proteins (FN and collagen I), but prevented the downregulation of PPARγ in RPMCs under HG conditions. HG treatment activated the nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) pathways. In addition, the NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), and the AP-1 inhibitor, SP600125, decreased the protein levels of FN, collagen I and PAI-1, suggesting a role for the NF-κB and AP-1 pathways in the regulation of ECM accumulation induced by HG in RPMCs. Notably, we demonstrated that pretreatment with pioglitazone significantly inhibited HG-induced NF-κB and AP-1 activation. Collectively, these results suggest that pioglitazone inhibits HG-induced ECM accumulation in RPMCs by increasing PPARγ expression, and by inhibiting the NF-κB and AP-1 pathways.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
NF-kappa B
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Fator de Transcrição AP-1
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Tiazolidinedionas
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Matriz Extracelular
Limite:
Animals
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article