Erythropoietin suppresses epithelial to mesenchymal transition and intercepts Smad signal transduction through a MEK-dependent mechanism in pig kidney (LLC-PK1) cell lines

被引：24

作者：

Chen, Chien-Liang ^{[1
,2
]}

Chou, Kang-Ju ^{[1
,2
]}

Lee, Po-Tsang ^{[1
,2
]}

Chen, Ying-Shou ^{[1
]}

Chang, Tsu-Yuan ^{[1
]}

Hsu, Chih-Yang ^{[1
]}

Huang, Wei-Chieh ^{[1
]}

Chung, Hsiao-Min ^{[1
,2
]}

Fang, Hua-Chang ^{[1
,2
]}

机构：

[1] Kaohsiung Vet Gen Hosp, Div Nephrol, Kaohsiung, Taiwan

[2] Natl Yang Ming Univ, Sch Med, Dept Med, Taipei 112, Taiwan

来源：

EXPERIMENTAL CELL RESEARCH | 2010年 / 316卷 / 07期

关键词：

Tumor growth factor-beta 1; Epithelial mesenchymal transition; Erythropoietin; TGF-BETA; ACTIVATION; DYSFUNCTION; INJURY; PROTECTS; FIBROSIS;

D O I：

10.1016/j.yexcr.2010.02.022

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Tumor growth factor-beta 1 (TGF beta 1) plays a pivotal role in processes like kidney epithelial-mesenchymal transition (EMT) and interstitial fibrosis, which correlate well with progression of renal disease. Little is known about underlying mechanisms that regulate EMT. Based on the anatomical relationship between erythropoietin (EPO)-producing interstitial fibroblasts and adjacent tubular cells, we investigated the role of EPO in TGF-beta 1-mediated EMT and fibrosis in kidney injury. Methods: We examined apoptosis and EMT in TGF-beta 1-treated LLC-PK1 cells in the presence or absence of EPO. We examined the effect of EPO on TGF-beta 1-mediated Smad signaling. Apoptosis and cell proliferation were assessed with flow cytometry and hemocytometry. We used Western blotting and indirect immunofluorescence to evaluate expression levels of TGF-beta 1 signal pathway proteins and EMT markers. Results: We demonstrated that ZVAD-FMK (a caspase inhibitor) inhibited TGF-beta 1-induced apoptosis but did not inhibit EMT. In contrast, EPO reversed TGF-beta 1-mediated apoptosis and also partially inhibited TGF-beta 1-mediated EMT. We showed that EPO treatment suppressed TGF-beta 1-mediated signaling by inhibiting the phosphorylation and nuclear translocation of Smad 3. Inhibition of mitogen-activated protein kinase kinase 1 (MEK 1) either directly with PD98059 or with MEK 1 siRNA resulted in inhibition of EPO-mediated suppression of EMT and Smad signal transduction in TGF-beta 1-treated cells. Conclusions: EPO inhibited apoptosis and EMT in TGF-beta 1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a mitogen-activated protein kinase-dependent inhibition of Smad signal transduction. (C) 2010 Elsevier Inc. All rights reserved.

引用

页码：1109 / 1118

页数：10

共 28 条

[1] Low-dose therapy with the long-acting erythropoietin analogue darbepoetin alpha persistently activates endothelial Akt and attenuates progressive organ failure [J].