PMID- 20202468
OWN - NLM
STAT- MEDLINE
DCOM- 20100504
LR  - 20121115
IS  - 1090-2422 (Electronic)
IS  - 0014-4827 (Linking)
VI  - 316
IP  - 7
DP  - 2010 Apr 15
TI  - Erythropoietin suppresses epithelial to mesenchymal transition and intercepts 
      Smad signal transduction through a MEK-dependent mechanism in pig kidney 
      (LLC-PK1) cell lines.
PG  - 1109-18
LID - 10.1016/j.yexcr.2010.02.022 [doi]
AB  - PURPOSE: Tumor growth factor-beta1 (TGF-beta1) 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-beta1-mediated EMT and 
      fibrosis in kidney injury. METHODS: We examined apoptosis and EMT in 
      TGF-beta1-treated LLC-PK1 cells in the presence or absence of EPO. We examined 
      the effect of EPO on TGF-beta1-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-beta1 signal pathway proteins and EMT markers. RESULTS: We demonstrated that 
      ZVAD-FMK (a caspase inhibitor) inhibited TGF-beta1-induced apoptosis but did not 
      inhibit EMT. In contrast, EPO reversed TGF-beta1-mediated apoptosis and also 
      partially inhibited TGF-beta1-mediated EMT. We showed that EPO treatment 
      suppressed TGF-beta1-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-beta1-treated cells. CONCLUSIONS: EPO inhibited apoptosis and EMT in 
      TGF-beta1-treated LLC-PK1 cells. This effect of EPO was partially mediated by a 
      mitogen-activated protein kinase-dependent inhibition of Smad signal 
      transduction.
CI  - Copyright 2010 Elsevier Inc. All rights reserved.
FAU - Chen, Chien-Liang
AU  - Chen CL
AD  - Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
FAU - Chou, Kang-Ju
AU  - Chou KJ
FAU - Lee, Po-Tsang
AU  - Lee PT
FAU - Chen, Ying-Shou
AU  - Chen YS
FAU - Chang, Tsu-Yuan
AU  - Chang TY
FAU - Hsu, Chih-Yang
AU  - Hsu CY
FAU - Huang, Wei-Chieh
AU  - Huang WC
FAU - Chung, Hsiao-Min
AU  - Chung HM
FAU - Fang, Hua-Chang
AU  - Fang HC
LA  - eng
PT  - Journal Article
DEP - 20100302
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Caspase Inhibitors)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Smad Proteins)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
RN  - 11096-26-7 (Erythropoietin)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.4.22.- (Caspases)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/pharmacology
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Caspase Inhibitors
MH  - Caspases/metabolism
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Down-Regulation/drug effects
MH  - Epithelium/*drug effects/physiology
MH  - Erythropoietin/*pharmacology
MH  - Kidney/*drug effects/metabolism/physiology
MH  - Kidney Tubules, Proximal/drug effects/metabolism/physiology
MH  - Mesoderm/*drug effects/physiology
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism/*physiology
MH  - Signal Transduction/drug effects
MH  - Smad Proteins/*antagonists & inhibitors/metabolism/physiology
MH  - Swine
MH  - Transforming Growth Factor beta1/antagonists & inhibitors/pharmacology
EDAT- 2010/03/06 06:00
MHDA- 2010/05/05 06:00
CRDT- 2010/03/06 06:00
PHST- 2008/07/16 00:00 [received]
PHST- 2010/02/19 00:00 [revised]
PHST- 2010/02/19 00:00 [accepted]
PHST- 2010/03/06 06:00 [entrez]
PHST- 2010/03/06 06:00 [pubmed]
PHST- 2010/05/05 06:00 [medline]
AID - S0014-4827(10)00084-4 [pii]
AID - 10.1016/j.yexcr.2010.02.022 [doi]
PST - ppublish
SO  - Exp Cell Res. 2010 Apr 15;316(7):1109-18. doi: 10.1016/j.yexcr.2010.02.022. Epub 
      2010 Mar 2.