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

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

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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, a-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 a-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.

Original languageEnglish
Article numbere109628
JournalPloS one
Volume9
Issue number10
DOIs
Publication statusPublished - 2014 Oct 2

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Hydroxymethylglutaryl-CoA Reductase Inhibitors
Epithelial-Mesenchymal Transition
Dialysis
Peritoneal Dialysis
dialysis
Simvastatin
Rats
peritoneum
Peritoneum
rats
cells
cadherins
fibronectins
Cadherins
Fibronectins
snails
Mevalonic Acid
Ascitic Fluid
rac1 GTP-Binding Protein
rhoA GTP-Binding Protein

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Chang, Tae Ik ; Kang, Hye Young ; Kim, Kyung Sik ; Lee, Sun Ha ; Nam, Bo Young ; Paeng, Jisun ; Kim, Seonghun ; Park, Jung Tak ; Yoo, Tae Hyun ; Kang, Shin Wook ; Han, Seung Hyeok. / The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells. In: PloS one. 2014 ; Vol. 9, No. 10.
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title = "The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells",
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, a-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 a-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.",
author = "Chang, {Tae Ik} and Kang, {Hye Young} and Kim, {Kyung Sik} and Lee, {Sun Ha} and Nam, {Bo Young} and Jisun Paeng and Seonghun Kim and Park, {Jung Tak} and Yoo, {Tae Hyun} and Kang, {Shin Wook} and Han, {Seung Hyeok}",
year = "2014",
month = "10",
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doi = "10.1371/journal.pone.0109628",
language = "English",
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The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells. / Chang, Tae Ik; Kang, Hye Young; Kim, Kyung Sik; Lee, Sun Ha; Nam, Bo Young; Paeng, Jisun; Kim, Seonghun; Park, Jung Tak; Yoo, Tae Hyun; Kang, Shin Wook; Han, Seung Hyeok.

In: PloS one, Vol. 9, No. 10, e109628, 02.10.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells

AU - Chang, Tae Ik

AU - Kang, Hye Young

AU - Kim, Kyung Sik

AU - Lee, Sun Ha

AU - Nam, Bo Young

AU - Paeng, Jisun

AU - Kim, Seonghun

AU - Park, Jung Tak

AU - Yoo, Tae Hyun

AU - Kang, Shin Wook

AU - Han, Seung Hyeok

PY - 2014/10/2

Y1 - 2014/10/2

N2 - 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, a-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 a-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.

AB - 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, a-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 a-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.

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