Low-dose paclitaxel ameliorates renal fibrosis by suppressing transforming growth factor-ß1-induced plasminogen activator inhibitor-1 signaling.
Nephrology (Carlton)
; 21(7): 574-82, 2016 Jul.
Article
em En
| MEDLINE
| ID: mdl-26869361
ABSTRACT
AIM:
To investigate the effect of microtubule stabilization with low-dose paclitaxel on renal fibrosis, focusing on the transforming growth factor-ß1 (TGF-ß1)-induced plasminogen activator inhibitor-1 (PAI-1) signaling cascade.METHODS:
Forty-eight rats were randomly assigned to four groups sham/vehicle, sham/paclitaxel, unilateral ureteral obstruction (UUO)/vehicle and UUO/paclitaxel. Rats were treated with a 0.3 mg/kg intraperitoneal dose of paclitaxel or vehicle twice per week for 14 days. Half of the rats in each group were sacrificed respectively on day 7 and 14 after operation. Inner medullar collecting duct (IMCD) cells stimulated with TGF-ß1 were incubated with 0, 1 and 2 nM paclitaxel for 24 and 72 hours. Histological changes were assessed using periodic acid-Schiff and Masson's trichrome. The TGF-ß1-induced PAI-1 signaling and status of extracellular matrix proteins were evaluated by western blot analysis.RESULTS:
In the UUO kidneys, paclitaxel significantly attenuated tubular damage and interstitial collagen deposition, as well as α-smooth muscle actin (α-SMA), TGF-ß1 and PAI-1 protein expression. Paclitaxel also inhibited the UUO-induced activation of Smad2/3 and c-Jun N-terminal kinase (JNK). However, paclitaxel treatment did not inhibit extracellular signal-regulated kinase 1/2 (ERK1/2) or p38 expression. In TGF-ß1-treated IMCD cells, treatment with 1 and 2 nM paclitaxel for 72 h reduced fibronectin, α-SMA and PAI-1 protein expression. Moreover, a 2 nM dose of paclitaxel for 24 h significantly inhibited the TGF-ß1-stimulated activation of Smad2/3, JNK and ERK1/2 in IMCD cells.CONCLUSION:
Paclitaxel at low non-cytotoxic doses ameliorates renal fibrosis by inhibiting multiple steps in the TGF-ß1-induced PAI-1 signaling including Smads and mitogen-activated protein kinases.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Paclitaxel
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Inibidor 1 de Ativador de Plasminogênio
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Moduladores de Tubulina
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Fator de Crescimento Transformador beta1
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Rim
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Nefropatias
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Nephrology (Carlton)
Ano de publicação:
2016
Tipo de documento:
Article