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

Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
Laboratory Investigation (Impact Factor: 3.68). 02/2010; 90(3):436-47. DOI: 10.1038/labinvest.2009.149
Source: PubMed


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.

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    • "Interestingly, low-dose paclitaxel has been shown to inhibit collagen-induced arthritis, hepatic fibrosis, and fibrosis associated with systemic sclerosis in severe combined immunodeficiency (SCID) mice.5–6,26 In kidneys, Zhang et al7 reported that low-dose paclitaxel (0.3 mg/kg, twice a week) significantly reduced tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction. Karbalay-Doust et al27 found that both taurine and paclitaxel (0.3 mg/kg/d) had a renoprotective role in the unilateral ureteral obstruction model and the latter was more effective. "
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    ABSTRACT: Paclitaxel (Taxol), one of the most important anticancer drugs, has been used for therapy of different types of cancers. Mechanistically, paclitaxel arrests cell cycle and induces cell death by stabilizing microtubules and interfering with microtubule disassembly in cell division. Recently, it has been found that low-dose paclitaxel seems promising in treating non-cancer diseases, such as skin disorders, renal and hepatic fibrosis, inflammation, axon regeneration, limb salvage, and coronary artery restenosis. Future studies need to understand the mechanisms underlying these effects in order to design therapies with specificity.
    Drug Design, Development and Therapy 02/2014; 8:279-84. DOI:10.2147/DDDT.S56801 · 3.03 Impact Factor
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    • "EMT is another important process affecting the population of interstitial fibroblasts which lose their epithelial phenotype and show the progressive development of a mesenchymal phenotype that leads to TEC damage and fibrosis in the kidney [11]. Many studies have demonstrated that TGF-í µí»½ promotes renal fibrosis through EMT by activation of Smad2/3 [12] [13] [14] and was counteracted with BMP-7 by motivation of Smad1/5/8 to maintain the epithelial phenotype of TECs [15] [16]. The expression of the mesenchymal phenotype in TECs and fibroblasts using S100A4 as a marker has been observed in many kidney diseases [17] [18]. "
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    ABSTRACT: This study aims to investigate the renoprotective effect of recombinant human erythropoietin (rhEPO) treatment could preserve tubular epithelial cell regeneration and ameliorate renal fibrosis by dual inhibition of stress-induced senescence and EMT in unilateral ureteric obstruction (UUO) mouse model. UUO or sham-operated mice were randomly assigned to receive rhEPO or vehicle treatment and were sacrificed on days 3, 7, and 14. Kidney specimens were fixed for histopathological and immunohistochemical study. The expression of S100A4, TGF- β 1, BMP-7, Smad2/3, Smad1/5/8, and p16(INK4a) was determined by western blot and real-time RT-PCR. Vehicle treated UUO mice had increased tubular atrophy and interstitial fibrosis within 3 to 14 days. An increase in TGF- β 1, Smad2/3, S100A4, and p16(INK4a) expression and a decrease in BMP-7 and Smad1/5/8 expression were observed in the obstructed kidneys. p16(INK4a) was positively correlated with TGF- β 1/Smad2/3 and negatively correlated with BMP-7/Smad1/5/8 in UUO mice. rhEPO treatment significantly suppressed the upregulation of TGF- β , Smad2/3, S100A4, and p16(INK4a) and preserved the downregulation of BMP-7 and Smad1/5/8, resulting in markedly reduced TA/IF compared to the vehicle treated mice. The renoprotective effects of rhEPO could ameliorate renal TA/IF by modulating senescence and EMT which could be a part of therapeutic option in patients with chronic kidney disease.
    11/2013; 2013(1):308130. DOI:10.1155/2013/308130
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    • "In contrast, certain studies have demonstrated that paclitaxel (PTX), one of the major anticancer agents that stabilizes microtubules and arrests the cell cycle in the G0/G1 and G2/M phases (11,12), inhibits the invasive ability of breast cancer cell lines when used in low-doses (13,14). Furthermore, certain studies have revealed that low-dose PTX inhibits TGF-β/Smad activity in fibrosis (15,16). Based on these findings, the present study hypothesized that low-dose PTX may inhibit the induction of EMT by TGF-β1 in the human cholangiocarcinoma CCKS-1 cell line. "
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    ABSTRACT: Epidermal-mesenchymal transition (EMT) confers an advantage to cancer cells by improving their invasive capacity and metastatic potential. This phenomenon by which epidermal cells change into mesenchymal cells and therefore acquire a higher ability to automaticity, is considered a key process in cancer development. Transforming growth factor-β (TGF-β) is a significant factor for accelerating EMT through the activation of proteins, including members of the Smad pathway. Furthermore, previous studies have shown that low-dose paclitaxel (PTX) inhibits EMT in certain cell lines, including those of cancer cells. The present study determined whether low-dose PTX was able to inhibit EMT in a human cholangiocarcinoma CCKS-1 cell line that had been treated with TGF-β1. First, the cytotoxic concentration of PTX for the CCKS-1 cells was identified to be ~5 nM by MTT assay and dead cell staining. Therefore, the concentrations of PTX were set as 1 nM, 2.5 nM and 5 nM for the subsequent experiments. In the morphological investigation, the CCKS-1 cells changed into a spindle morphology and became separated by the administration of TGF-β1. However, low-dose PTX inhibited these changes and the morphology resembled the control cells in a dose-dependent manner. Similarly, immunofluorescence and immunoblotting investigations revealed that the CCKS-1 cells expressed mesenchymal markers following the administration of TGF-β1. However, low-dose PTX inhibited the expression of the mesenchymal markers and the CCKS-1 cells expressed the epithelial marker, E-cadherin. In particular, a concentration-dependent effect was observed in the immunoblotting experiments. These results show that PTX may be able to inhibit EMT in cancer cells, depending on the dose concentration.
    Oncology letters 10/2013; 6(4):915-920. DOI:10.3892/ol.2013.1494 · 1.55 Impact Factor
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