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The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells.

Authors
 Tae Ik Chang  ;  Hye Young Kang  ;  Kyung Sik Kim  ;  Sun Ha Lee  ;  Bo Young Nam  ;  Jisun Paeng  ;  Seonghun Kim  ;  Jung Tak Park  ;  Tae Hyun Yoo  ;  Shin Wook Kang  ;  Seung Hyeok Han 
Citation
 PLoS One, Vol.9(10) : e109628, 2014 
Journal Title
 PLoS One 
ISSN
 1932-6203 
Issue Date
2014
MeSH
Animals ; Cells, Cultured ; Epithelial Cells/cytology* ; Epithelial Cells/drug effects* ; Epithelial Cells/metabolism ; Epithelial-Mesenchymal Transition/drug effects* ; Fibronectins/metabolism ; Humans ; Hypolipidemic Agents/pharmacology* ; Male ; Mevalonic Acid/metabolism ; Monomeric GTP-Binding Proteins/metabolism ; Peritoneum/cytology* ; Peritoneum/drug effects ; Peritoneum/metabolism ; Rats, Sprague-Dawley ; Signal Transduction/drug effects ; Simvastatin/pharmacology* ; Terpenes/metabolism
Abstract
BACKGROUND: Statins have recently been highlighted for their pleiotropic actions distinct from cholesterol-lowering effects. Despite this interest, it is currently unknown whether statin therapy inhibits peritoneal dialysis (PD)-related epithelial-mesenchymal transition (EMT). METHODS: In vitro, human peritoneal mesothelial cells (HPMCs) were exposed to 5.6 mM glucose (NG) or 100 mM glucose (HG) with or without simvastatin (1 µM). In vivo, PD catheters were inserted into 32 Sprague-Dawley rats, and saline (C, n = 16) or 4.25% peritoneal dialysis fluid (PDF) (PD, n = 16) was infused for 4 weeks. Eight rats from each group were treated with 5 mg/kg/day of simvastatin intraperitoneally. Changes in the protein expression of EMT markers such as E-cadherin, α-SMA, Snail, and fibronectin in HPMCs and the peritoneum were evaluated by Western blot analysis and immunofluorescence or immunohistochemical staining. We also explored whether activation of the mevalonate pathway and its downstream small GTPases were involved in dialysis-related peritoneal EMT and could be inhibited by statin treatment. RESULTS: Compared to NG cells, E-cadherin expression was significantly decreased, while α-SMA, Snail, and fibronectin expression were significantly increased in HPMCs exposed to HG, and these changes were abrogated by simvastatin (p<0.05). In addition, the cobblestone-like appearance of normal HPMCs was converted into a fibroblast-like morphology after HG treatment, which was reversed by simvastatin. These EMT-like changes were also observed in HPMCs treated with geranyl-geranyl pyrophosphate (5 µM). HG significantly increased the protein expression of RhoA and Rac1 in the membrane fractions, and these increases were ameliorated by simvastatin (p<0.05). In PD rats, E-cadherin in the peritoneum was significantly decreased, whereas α-SMA, Snail, and fibronectin expression were significantly increased (p<0.05) compared to C rats. The thickness of the mesothelial layer in the peritoneum were also significantly greater in PD rats than in C rats (p<0.05). These changes of the peritoneum in PD rats were significantly attenuated by simvastatin. CONCLUSION: This study demonstrated that PD-related EMT was mediated via the mevalonate pathway, and statin treatment inhibited the EMT changes in HG-treated HPMCs and PDF-stimulated PD rats. These findings suggest that statins may be a promising therapeutic strategy for preservation of peritoneal membrane integrity in long-term PD patients.
Files in This Item:
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DOI
10.1371/journal.pone.0109628
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Shin Wook(강신욱) ORCID logo https://orcid.org/0000-0002-5677-4756
Kang, Hye Young(강혜영)
Kim, Kyung Sik(김경식) ORCID logo https://orcid.org/0000-0001-9498-284X
Nam, Bo Young(남보영)
Park, Jung Tak(박정탁) ORCID logo https://orcid.org/0000-0002-2325-8982
Yoo, Tae Hyun(유태현) ORCID logo https://orcid.org/0000-0002-9183-4507
Lee, Sun Ha(이순하)
Chang, Tae Ik(장태익)
Paeng, Ji Sun(팽지선)
Han, Seung Hyeok(한승혁) ORCID logo https://orcid.org/0000-0001-7923-5635
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/138318
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