Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-β/Smad activity

被引：101

作者：

Zhang, Dongshan ^{[1
,2
]}

Sun, Lin ^{[1
]}

Xian, Wang ^{[3
]}

Liu, Fuyou ^{[1
]}

Ling, Guanghui ^{[1
]}

Xiao, Li ^{[1
]}

Liu, Yanhong ^{[1
]}

Peng, Youmin ^{[1
]}

Haruna, Yoshisuke ^{[4
,5
]}

Kanwar, Yashpal S. ^{[4
,5
]}

机构：

[1] Cent S Univ, Xiangya Hosp 2, Dept Nephrol, Changsha 410011, Hunan, Peoples R China

[2] Cent S Univ, Xiangya Hosp 2, Dept Emergency, Changsha 410011, Hunan, Peoples R China

[3] Cent S Univ, Xiangya Hosp 2, Dept Neurol, Changsha 410011, Hunan, Peoples R China

[4] Northwestern Univ, Dept Pathol, Chicago, IL 60611 USA

[5] Northwestern Univ, Dept Med, Chicago, IL 60611 USA

来源：

LABORATORY INVESTIGATION | 2010年 / 90卷 / 03期

关键词：

TGF-beta; UUO; tubulointerstitial fibrosis; microtubule; paclitaxel; Smad; INTEGRIN-LINKED KINASE; EXTRACELLULAR-MATRIX; MESENCHYMAL TRANSITION; GENE-TRANSFER; BETA; EXPRESSION; SMAD3; ILK; TRANSDIFFERENTIATION; MECHANISMS;

D O I：

10.1038/labinvest.2009.149

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Transforming growth factor-beta (TGF-beta) has a pivotal function in the progression of renal fibrosis in a wide variety of renal diseases. Smad proteins have been identified to have an important function in regulating the expression of extracellular matrix (ECM) proteins through TGF-beta signaling pathway. Aberrant TGF-beta/Smad signaling can be modulated by stabilization of microtubules with paclitaxel. In this study, we investigated if paclitaxel can attenuate tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction (UUO). Rats in groups of six were subjected to UUO and received low-dose intraperitoneal injection of paclitaxel (0.3 mg/kg) twice a week. They were killed at day 7 and 14 after UUO or Sham operation. TGF-beta signaling cascade and status of various ECM proteins were evaluated by RT-PCR, western blotting and immunohistochemical or immunofluorescence staining. The paclitaxel treatment markedly suppressed Smad2 and Smad3 phosphorylation. This was associated with attenuated expression of integrin-linked kinase, collagens I and III, fibronectin (FN) and alpha-smooth muscle actin, and a substantial decrease in renal fibrosis in animals that underwent UUO and received paclitaxel. These data indicate that the low-dose paclitaxel ameliorates renal tubulointerstitial fibrosis by modulating TGF-beta signaling, and thus, the paclitaxel may have some therapeutic value in humans.

引用

页码：436 / 447

页数：12

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